TETRAHYDRO-1H-PYRIDO [3,4-b]INDOLE ANTI-ESTROGENIC DRUGS

ABSTRACT

The present disclosure provides tetrahydro-1H-pyrido[3,4-b]indole compounds or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer, N-oxide and/or substituted derivative or, optionally in a pharmaceutical composition, for the modulation of disorders mediated by estrogen, or other disorders as more fully described herein.

FIELD OF THE DISCLOSURE

This invention is in the field of pharmaceuticals, and is in particularnovel tetrahydro-1H-pyrido[3,4-b]indole compounds and their medicaluses, including as estrogen receptor modulators and for medicalconditions that would benefit from an anti-estrogenic drug, and salts(including pharmaceutically acceptable salts), prodrugs and derivativesthereof and compositions thereof.

BACKGROUND

Estrogen receptor modulators are a class of compounds that act on theestrogen receptor. These compounds can be pure agonists (mimickingestrogen), pure antagonists, or mixed agonist-antagonists (sometimesreferred to as Selective Estrogen Receptor Modulators (SERMs)). Forexample, estradiol is a pure agonist, fulvestrant is a completeantagonist, and tamoxifen and raloxifene are SERMs.

Most breast cancers express estrogen receptors (ER), and their growth isdriven by the action of estrogen at its receptors, primarily at ERalpha. This type of cancer is treated with an estrogen receptorantagonist, which competes with estrogen for binding to the receptor,but does not activate it, preventing estrogen driven growth. Partialanti-estrogens such as raloxifene and tamoxifen retain someestrogen-like effects, including an estrogen-like stimulation of uterinegrowth, and also, in some cases, an estrogen-like action during breastcancer progression which stimulates tumor growth. In contrast,fulvestrant, a complete anti-estrogen, is free of estrogen-like actionon the uterus and is effective in tamoxifen-resistant tumors. A recentstudy also suggests that fulvestrant is substantially superior to thearomatase inhibitor anastrozole in treating metastatic breast cancer(Robertson et al. J Clin Oncol (2009) 27(27):4530-5).

Estradiol is a naturally-occurring female estrogenic hormone. Raloxifenewas disclosed by Eli Lilly in 1981 (U.S. Pat. Nos. 4,418,068; 5,478,847;5,393,763; and 5,457,117) for prevention of breast cancer and treatmentof osteoporosis. Fulvestrant was disclosed by Imperial ChemicalIndustries (ICI) in 1983 (U.S. Pat. No. 4,659,516, expired in 2007 witha patent term extension; U.S. Pat. Nos. 6,774,122 and 7,456,160).Tamoxifen was also disclosed by ICI in the '516 patent. Tamoxifen wasdeveloped for the treatment of breast cancer on the basis of strongantagonism of estrogen action in mammary tissue (Jordan, J. Cell.Biochem. 51 (1995)).

The degree of anti-estrogenicity is often assayed by exposing female,immature (preferably ovariectomized) rodents to test doses of thecompound both in the absence (agonist mode) and presence (antagonistmode) of estrogen. Tamoxifen and other partial anti-estrogens stimulateuterine weight gain in the agonist mode and only partly blockestrogen-driven uterine weight gain in the antagonist mode. Fulvestrantand other complete anti-estrogens do not stimulate uterine weight gainin the agonist mode and completely block estrogen-driven weight gain inthe antagonist mode. The induction of estrogen-regulated alkalinephosphatase expression in human uterine cancer cell growth in culturecan be used to distinguish partial and complete anti-estrogenicity andcorrelates well with the rodent weight gain assay. See U.S. Pat. No.9,018,244.

Tamoxifen and fulvestrant both inhibit cultured human breast cancer cellproliferation provoked by estrogen. However, fulvestrant more fullyinhibits the proliferation when provoked with growth factors, especiallyof the insulin/insulin-like growth factor family. Thus the inhibition ofgrowth-factor driven breast cancer cell proliferation and the effect onuterine weight provide two assays which can distinguish between completeand partial anti-estrogens.

Compounds that act by degrading the estrogen receptor are sometimesreferred to as “SERDs” (Selective Estrogen Receptor Degraders). Whiletamoxifen binding stabilizes the estrogen receptor, fulvestrant andchemically related antiestrogens, such as ICI-164384 and RU-58668, causedegradation of the estrogen receptor. The ability to induce degradationof the receptor is a factor that differentiates the behavior oftamoxifen and fulvestrant and may be desirable in a drug to treat breastcancer.

Fulvestrant incorporates a core of 17-beta estradiol. The estradiol coreblocks oral absorption and the long flexible aliphatic side chain leadsto poor solubility of the drug. Together, these aspects provide for poororal bioavailabity of fulvestrant and the drug must be administered viainjection. Two 5 ml intramuscular depot inj ections, one into eachbuttock, must be administered monthly by a health professional.Furthermore, it is unclear whether these two injections providesufficient drug exposure for optimal action. The drug does not appear towork in pre-menopausal women.

Some compounds, such as GW-5638 (Wu et al, Mol Cell., 18, 413 (2005)),degrade the receptor but are partial estrogens, rather than completeanti-estrogens. Thus the ability to degrade the estrogen receptor doesnot ensure complete antiestrogenicity.

In 1990, a family of high-affinity benzopyran anti-estrogens wasdiscovered by Kapil and coworkers. (Sharma et al. (1990) J Med Chem,33(12):3222-9; Sharma et al. (1990) J Med Chem, 33(12):3216-22). Thisresearch resulted in the discovery of the drug candidate acolbifene.

In June 2011, Aragon Pharmaceuticals filed PCT/US2011/039669 (publishedDec. 15, 2011 as WO2011/156518) which claimed priority to U.S.Provisional Application 61/353,531 titled “Estrogen Receptor Modulatorsand Uses Thereof.” Aragon disclosed additional benzopyran derivativesand at least 71 acolbifene analogs for treatment of tamoxifen-resistantbreast cancer. Patent filings assigned to Aragon also include U.S. Pat.Nos. 8,455,534 and 8,299,112. Aragon was acquired by Johnson & Johnsonin 2013 for its line of prostate anti-androgen drugs, and Aragoncontinued with its anti-estrogenic developmental drugs under the nameSeragon Pharmaceuticals, Inc. Seragon is now advancing SERD ARN-810 inclinical trials for postmenopausal women with locally advanced ormetastatic estrogen receptor positive breast cancer. Patent filings bySeragon in this area include U.S. Pat. Nos. 9,078,871; 8,853,423; and8,703,810; as well as US 2015/0005286 and WO 2014/205136 filed by Govek,et al., and WO 2014/205138 filed by Kahraman et al. Seragon was acquiredby Genentech in 2014.

Kushner et al. in WO 2013/090921 and US2013/0178445, filed Dec. 17, 2012and assigned to Olema Pharmaceuticals, describe OP-1038(3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol)and OP-1074((2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-chromen-7-ol),as well as pharmaceutical compositions and methods of use. Additionalpatent filings by Olema in the area of anti-estrogenic compounds includeWO 2014/203129 and WO 2014/203132.

Astra Zeneca is currently developing AZD9496 a novel, oral selectiveestrogen receptor down-regulator (SERD) in patients with estrogenreceptor positive (ER+) breast cancer. See, WO 2014/191726. Thestructure of AZD9496 is illustrated below:

Additional indole, benzopyran, and 2H-chromene compounds are disclosedin WO 2012/084711, WO 2002/013802; WO 2002/004418; WO 2002/003992; WO2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276; U.S. Pat. No.6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392; 6,756,401; US2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US 2001/0056099; U.S.Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S. Pat. No. 6,005,102;EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497 and 5,880,137.

The object of the present invention is to provide new anti-estrogeniccompounds with advantageous properties for the treatment of medicaldisorders that are mediated or affected by an estrogen receptor andpharmaceutical compositions and uses thereof.

SUMMARY OF THE INVENTION

The present invention provides specifictetrahydro-1H-pyrido[3,4-b]indole compounds of Formula I havingadvantageous properties for the treatment of medical disorders in ahost, typically a human, that are modulated or affected by an estrogenreceptor. These tetrahydro-1H-pyrido[3,4-b]indole compounds have asignificant inhibitory effect on estrogen receptors at nanomolarconcentration and have minimal residual estrogenic effects.

The present invention particularly provides two specific compounds,Compound B((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole)and Compound C((1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole),whose structures are surprisingly different from prior compoundsdescribed in the art as being useful estrogen receptor antagonists, andin fact contain specific structural features that teachings in the artaffirmatively indicated were undesirable. Specifically, Compounds B andC, unlike AZD9496, described above, lack the difluorophenyl bridge, asillustrated below.

The present disclosure describes these Compounds B and C and variousmethods and compositions relating thereto. Furthermore, the presentdisclosure documents certain surprising and unexpected attributes ofthese compounds, even when compared with structurally similar agents.Compounds B and C are both encompassed within Formula I, provided by thepresent invention:

wherein:

-   -   X is —CH₂— or —O—;    -   Y is

-   -   R¹, R², R³ and R⁴ are each independently selected from hydrogen        or halo;    -   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₀-C₄(C₃-C₆cycloalkyl) or C₁-C₆heteroalkyl;    -   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl or        C₀-C₄(C₃-C₆cycloalkyl);    -   R⁷ and R⁸ are each independently selected from hydrogen or        C₁-C₆alkyl;

or a pharmaceutically acceptable salt or a composition thereof.

Compounds B and C, as documented herein, have particularly notablestructural aspects, and furthermore are characterized by unexpected anddesirable functional attributes, even with respect to other compoundshaving structures within the scope of Formula I.

As is readily apparent from the structures of Compounds B and C, each ofR¹, R², R³ and R⁴ is H. In addition to describing the particularsignificance of Compounds B and C, the present disclosure specifically,and more generally, provides compounds of Formula I wherein each of R¹,R², R³ and R⁴ is H.

Particular compounds within Formula I that are exemplified hereininclude Compound A, which is(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(3-fluoro-4-((-propylazetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole,Compound B, which is(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole,Compound C, which is(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole,and Compound D, which is(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.

The structures of Compound A, Compound B, Compound C, and Compound D areillustrated below.

In each of these compounds,

moieties are bonded to a tetrahydro-1H-pyrido[3,4-b]indole core via aphenyl or fluoro-substituted phenyl bridge. Of note, only one of thesecompounds, Compound D, includes a difluoro substitution of the type thatthe AstraZeneca disclosure teaches is critical. Compound D was reportedby Goodacre, et al. in PCT Application Publication No. WO 2016/097072,and is otherwise referred to herein as “Goodacre Compound 102.” Each ofat least Compounds A-C, therefore, has a structure that explicitly lacksa moiety taught by the art as essential for estrogen receptorantagonists.

The present disclosure documents that each of Compounds A-D has certainadvantageous anti-estrogen activities. For example, while AZD9496 is apotent inhibitor of E2-induced transcription in breast cells with anIC₅₀=1.3 nM and E2-stimulated proliferation in breast cells with anIC₅₀=0.2 nM, AZD9496 has approximately 10-fold greater estrogen-likeactivity as both an alkaline phosphatase (AP) agonist and antagonist incomparison to Compounds A-D. Advantageous activities of Compound A,Compound B, Compound C and Compound D are illustrated in Table 1.

TABLE 1 MCF-7 Prolifera- AP AP ERE-Luc tion Agonist Antagonist IC₅₀ IC₅₀Act. Act. Compound (nM) (nM) (% of E2) (% of E2) A 2.96 7.58 3.96 3.15 B4.35 4.53 2.18 1.96 C 10.7 14.5 3.1 2.5 D 10.0 8.4 3.37 4.07 AZD9496 0.21.3 35 33

Compounds B and C show comparable activity to fulvestrant, anintramuscularly injected antiestrogen shown to be superior to otherhormonal therapies for treating first line metastatic human breastcancer. Compounds B and C have potency similar to fulvestrant inblocking estrogen driven gene expression and proliferation of humanbreast cancer cells. The potency of Compounds B and C, therefore, issuperior to AZD9496. See FIG. 2A.

The present disclosure exemplifies a variety of additional interestingand desirable activities for Compound B. For example, Compound Binhibited E2-induced transcription in breast cells with an IC₅₀=4.35 nM.Compound B also demonstrated inhibition of E2-stimulated proliferationin breast cells with an IC₅₀=4.53 nM. When ECC-1 cells were incubatedwith Compound B, the cells had only 2.18% of the AP activity that thecells would have if AP activity were normalized to the affect that 500pM 17β-estradiol has on ECC-1 cells. When ECC-1 cells were co-treatedwith Compound B and 500 pM 17β-estradiol, the ECC-1 cells exhibited only1.96% of the activity that 17β-estradiol would produce.

Compounds provided by the present invention can be prepared, if desired,as a pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, rotamer, N-oxide or X, Y, R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and/or R⁸ substituted derivative optionally in a pharmaceuticallyacceptable composition to treat a disorder that is modulated or affectedby an estrogen receptor, including those treatable with ananti-estrogenic agent.

In certain embodiments, a compound is disclosed having Formula I(a):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is disclosed having Formula I(b):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is disclosed having Formula I(c):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound is disclosed having Formula I(d):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

Compounds provided by the present invention can be prepared as is or asa pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, rotamer or N-oxide, optionally in apharmaceutically acceptable composition, to treat a disorder that ismodulated or affected by an estrogen receptor in a human or other hostin need thereof. In some embodiments, a compound of Formula I isprovided as a prodrug.

In some embodiments, a compound of Formula I has at least one isotopicsubstitution, and in particular, for example, at least one substitutionof deuterium for hydrogen. In one embodiment, the deuterium can be boundin a location of bond breakage during metabolism (an α-deuterium kineticisotope effect) or next to or near the site of bond breakage (aβ-deuterium kinetic isotope effect).

Examples of disorders that can be treated with compounds describedherein or their pharmaceutically acceptable salts, prodrugs, etc. orcompositions thereof include, but are not limited to, local, advanced ormetastatic breast cancer that is positive for expression of estrogenreceptors, progesterone receptors or both. Compounds may be administeredprior to surgery or following surgery to decrease the risk of recurrenceor to treat remaining tumor. Compounds described herein are useful asadjunctive therapy after or instead of chemotherapy, radiation orsurgery. They are also useful for the prevention of breast cancer inwomen at high risk for an estrogen modulated tumor or for the treatmentof other cancers and overgrowth diseases of estrogen-receptive tissue,such as the female reproductive tract including ovarian, endometrial,and vaginal cancer and endometriosis.

In some embodiments, the cancer, such as breast cancer, is in apostmenopausal woman who has relapsed or progressed following therapy.In other embodiments, the cancer, such as breast cancer in apostmenopausal woman, has progressed in the presence of endocrinetherapy. In yet other embodiments, the cancer, including in apostmenopausal woman, has previously progressed in the presence oftherapy with an aromatase inhibitor, such as aminoglutethimide,testolactone, anastrozole, letrozole, exemestane, vorozole, formestane,fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatrien-3,17-dione, or4-androstene-3,6,17-trione. In some embodiments, the aromatase inhibitoris anastrozole, letrozole, or exemestane.

In some embodiments, a compound of the present invention is used totreat estrogen or progesterone receptor negative breast cancer.

Compounds provided herein can be used as the initial treatment of anestrogen modulated tumor for example, in patients who have neverreceived previous hormonal therapy for advanced breast cancer, either byitself or in combination with one or more other anti-cancer agents,including targeted therapies, for example, a targeted therapy such as anmTOR inhibitor such as everolimus or rapamycin, a CDK4/6 inhibitor suchas palbociclib (PD-0332991) (Pfizer), Abemaciclib (LY2835219) (Lilly) orLEE001 (Novartis), herceptin, an antibody to or inhibitor of PD-1,PD-L1, or CTLA-4, or an inhibitor of or antibody to EGFR, PGFR or IGFR.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent or alternating administration.

Compounds provided by the present invention are also useful as adjuvanttherapy after surgery to prevent recurrence. Such adjuvant use is oftenadministered for several years, for instance up to 5 years, or 10 yearsafter surgery and/or associated chemotherapy and radiotherapy have beenconcluded.

Compounds provided by the present invention are useful for theprevention of breast cancer in women at high risk and can be taken forany desired time period, including indefinitely. For example, a patient,typically a woman, with a family history of breast cancer, or who hasbeen determined to carry a mutation in the BRCA1 or BRCA2 or other genethat predisposes a patient to breast cancer may choose to use suchpreventative treatment instead of a mastectomy or other intervention.Compounds described herein are also useful as neoadjuvants to shrinklarge tumors prior to surgical removal, both to enable breastconservative surgery and to reduce the risk of recurrence.

Selective estrogen receptor modulators (SERMs) are also useful forhormonal therapy for postmenopausal women in particular to treat orprevent osteoporosis. In some embodiments, a compound of the presentinvention is used to treat osteopenia, osteoporosis, or a related bonedisorder, optionally in combination with an estrogen, SERM or partialanti-estrogen such that the anti-estrogen prevents adverse action of thetotal or partial estrogen on the uterus and other tissues.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description. Allvariations and modifications of the disclosed invention are consideredwithin the scope of this invention.

The present invention includes at least the following features:

(a) a compound of Formula I as described herein, and a pharmaceuticallyacceptable salt solvate, hydrate, prodrug, stereoisomer, tautomer,rotamer or N-oxide thereof (each of which and all subgenuses and speciesthereof considered individually and specifically described);

(b) a compound of Formula I as described herein, and a pharmaceuticallyacceptable salt solvate, hydrate, prodrug, stereoisomer, tautomer,rotamer or N-oxide thereof for use in treating or preventing disordersmodulated or affected by an estrogen receptor in a human or other hostin need thereof and other disorders described further herein;

(c) use of a compound of Formula I, and a pharmaceutically acceptablesalt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer orN-oxide in the manufacture of a medicament for use in treating orpreventing a disorder that is modulated or affected by an estrogenreceptor in a human or other host in need thereof and other disordersdescribed further herein;

(d) a process for manufacturing a medicament intended for thetherapeutic use for treating or preventing disorders modulated oraffected by an estrogen receptor in a human or other host in needthereof and other disorders described further herein characterized inthat a compound of Formula I as described herein is used in themanufacture;

(e) a pharmaceutical formulation(s) comprising an effectivehost-treating amount of a compound of Formula I or a pharmaceuticallyacceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer,rotamer or N-oxide thereof together with a pharmaceutically acceptablecarrier or diluent;

(f) a compound of Formula I as described herein in substantially pureform, including substantially isolated from other chemical entities(e.g., at least 90 or 95%);

(g) processes for the manufacture of compounds of Formula I and salts,compositions, dosage forms thereof; and

(h) processes for the preparation of therapeutic products that containan effective amount of a compound of Formula I, as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a plot of the free drug concentration in BALB/c mice, at adosage of 5 mg/kg for Compound B and Goodacre Compound 107. The x-axisdepicts time in hours, and the y-axis depicts the concentration inpg/ml.

FIG. 1B is a plot of the free drug concentration in BALB/c mice, at adosage of 5 mg/kg for Compound C and Goodacre Compound 102. The x-axisdepicts time in hours, and the y-axis depicts the concentration inpg/ml.

FIG. 2 is a plot of the amount of estrogen-receptor α (ER-α) expression% compared to the concentration of compound provided, measuredlogarithmically.

FIG. 3 is a plot of the amount luciferase activity % compared to theconcentration of compound provided, measured logarithmically.

FIG. 4 is a plot of the amount of cell proliferation % compared to theconcentration of compound provided, measured logarithmically.

FIG. 5A is a plot measuring the % change in tumor size in xenograftedmice after 49 days.

FIG. 5B is a waterfall plot measuring the % change in tumor size inxenografted mice after 49 days.

FIG. 6A is a plot of the % estrogenic response in for the compoundsdepicted within as agonists without the presence of estrogen, ascompared to the concentration of the depicted compound, measuredlogarithmically.

FIG. 6B is a plot of the % estrogenic response in for the compoundsdepicted within as antagonists in the presence of estrogen, as comparedto the concentration of the depicted compound, measured logarithmically.

FIG. 6C provides depictions of the compounds examined in FIGS. 6A-6B.

FIG. 7 is the product of an estrogen degradation assay, measuring theability of specific compounds to degrade the estrogen receptor in MCF-7cells.

DETAILED DESCRIPTION OF THE INVENTION

Efforts to develop treatments for disorders such as breast cancer focuson interactions with estrogen receptors to ultimately inactivate thereceptor, either through competitive binding, or through degradation ofthe receptor. Compounds that compete with estrogen for receptor binding,and inhibit receptor activity, are known as “antiestrogens.”

Recent development of antiestrogens by AstraZeneca has focused aroundthe compound AZD9496, which recently entered clinical trials. See PCTApplication Publication No. WO 2014/191726.

AZD9496 comprises a difluorophenyl bridge, which was unlike otherantiestrogens in development at the time. AstraZeneca demonstrated,however, that this difluorophenyl bridge was necessary for increasingpotency overall (e.g., as assessed by one or more of increased bindingto isolated receptor, enhanced degradation of the estrogen receptor,more effective inhibition of estrogen-induced expression of theprogesterone receptor gene, and/or increased inhibition of proliferationof human breast cancer cell). Potency of compounds with thedifluorophenyl bridge was found to be 5- to 10-fold higher than that ofanalogous compounds which lacked the difluorophenyl bridge. See PCTApplication Publication No. WO 2014/191726, Table A (page 29).Specifically, AstraZeneca documented that compound AZD9496 (Example 1),has better ER binding IC₅₀ and ER down regulation IC₅₀ values thanExample 2, depoicted below, which lacks the difluorphenyl bridge.

WO 2014/ ER binding ER down regulation 191726 Example IC₅₀ value IC₅₀value 1 <0.64 0.14 2 1 0.85

Further, a published study by De Savi, et al., confirms the significanceof the difulorophenyl bridge in the AstraZeneca compounds. See De Savi,et al. “Optimization of a Novel Binding Motif to(E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylicAcid (AZD9496), a Potent and Orally Bioavailable Selective EstrogenReceptor Downregulator and Antagonist,” J. of Med. Chem., 58(20):8128-8140 (2015) (hereinafter “De Savi”). There, the authorscompared compound 30b (corresponding to AZD9496) to a number ofcompounds including compound 29b (corresponding to Example 2 from WO2014/191726) to assess ER binding, ER downregulation, PR agonism, PRantagonism, and MCF7 antiproliferation. See De Savi, supra, page 8130,Table 1. There, De Savi reported data illustrating that the presence ofthe fluoro substitution on the phenyl bridge was necessary for potencyin these assays, as shown in an excerpt of Table 1, provided below:

ER MCF ER down- PR PR anti- binding regulation agonist antagonismproliferation Entry pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ pIC₅₀ 29b   9 (±0.11) 9.07(±0.08) <5.5 8.46 (±0.12) 9.49 (±0.15) 30b 9.17 (±0.07) 9.86 (±0.03)<5.5 9.55 (±0.06) 10.4 (±0.05)

Therefore, as these two compounds (AZD9496 and Example 2 from WO2014/191726) are structurally identical to one another except for thedifluoro substitution, the teachings provided by AstraZeneca clearlyindicate that difluoro substitution is necessary for overall potencyand/or activity.

In light of these findings, subsequent development of antiestrogenstended to incorporate the same or similar difluorophenyl linkers intocompounds. For example, a patent application filed by Genentech anddirected to structurally similar compounds was published on Jun. 23,2016. See PCT Application Publication No. WO 2016/097072. While thegenera described therein are broad, almost all of the reported compoundscomprise the same difluorophenyl moiety, such as Compounds 102 and 107(also referred to as “Goodacre Compound 102” and “Goodacre Compound107,” respectively, below). See PCT Application Publication No. WO2016/097072, Tables 1 and 2 on page 33, et seq. Goodacre Compound 102 isalso referred to as “Compound D” above.

The present disclosure further discloses certain advantageousanti-estrogen activities of Compounds B and C. Advantageous activitiesof Compound B and Compound C as compared to Fulvestrant, AZD9496, andGoodacre Compounds 102 and 107 are illustrated in Table 2 and Table 3.

TABLE 2 Induction of Inhibition of Inhibition of Inhibition of AlkalineE2-stimulated E2-stimulated E2-stimulated Phosphatase AP (attranscription proliferation in (AP) 100 nM dose) in breast cells breastcells n % E2 SD n % E2 SD n pIC₅₀ SD n pIC₅₀ SD Fulvestrant 53 −0.041.36 53 -0.09 1.28 41 8.72 0.24 45 8.58 0.25 AZD-9496 14 39 13 12 39.116.7 12 9.20 0.28 16 8.73 0.31 Compound 21 1.78 1.22 19 1.56 1.23 208.36 0.25 25 8.11 0.17 B Goodacre 7 0.00 1.49 7 1.03 0.94 5 8.36 0.25 88.12 0.08 Compound 107 Compound 10 1.71 1.71 8 1.76 0.80 11 8.09 0.14 147.93 0.13 C Goodacre 5 4.45 2.95 4 3.98 0.50 7 8.02 0.16 7 7.98 0.06Compound 102

As can be seen from Table 2, Compounds B and C show improved APantagonist activity (i.e, are more complete antiestrogens) relative toAZD9496 and to Goodacre Compoound 102. Of note, Goodacre Compound 102,which structure includes the difluoro substitution taught by AstraZenecato be essential to activity, shows the worst AP agonist and antagonistactivity.

Even more importantly, Compounds B and C, which lack the difluorophenylbridge, exhibit a higher free fraction in mouse and human plasma thanGoodacre Compounds 102 and 107, structurally similar compounds thatcontain the difluorophenyl bridge. When each of these compounds isdelivered to mice by oral gavage, and when free fraction is taken intoaccount Compound B and Compound C have a substantially higher oral drugexposure than an equal dose of Compounds 107 and 102 (FIGS. 1A-1B).Compound B and Compound C are of similar potency in binding to isolatedestrogen receptor alpha (Table 3), in degrading estrogen receptor alpha(FIG. 2), and in blocking estrogen driven breast cancer cell geneexpression (FIG. 3) and proliferation (FIG. 4) when compared to GoodacreCompounds 102 and 107. In total, the observations of equivalent orsuperior potency of Compounds B and C combined with the observations ofsuperior free drug exposure per identical dose indicate that Compounds Band C are likely to be more effective than Goodacre Compounds 102 and107 per unit of oral dose in blocking estrogen receptor drivenpathological conditions such as estrogen-driven breast cancer.

Accordingly, the present invention is based on the discovery thatspecific tetrahydro-1H-pyrido[3,4-b]indole compounds of Formula I (inthe form of a mixture of stereoisomers and also the pure enantiomers)have advantageous properties for the treatment of medical disorders thatare modulated or affected by an estrogen receptor.

The present invention particularly provides two specific compounds,Compound B((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole)and Compound C((1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole),whose structures are surprisingly different from prior compoundsdescribed in the art as being useful estrogen receptor antagonists, andin fact contain specific structural features that teachings in the artaffirmatively indicated were undesirable. Specifically, Compounds B andC, unlike AZD9496, and Goodacre Compounds 102 and 107 described above,lack the difluorophenyl bridge, as illustrated below.

TABLE 3 Relative change in ERα % free drug ERα levels in breast cells inplasma binding n % Veh pIC₅₀ human mouse pIC₅₀ Fulvestrant 40 28 8.640.001 8.64 AZD-9496 15 49 9.43 0.308 0.214 9.43 Compound B 13 45 8.570.036 0.027 8.57 Goodacre 4 44 8.55 0.013 0.012 8.55 Compound 107Compound C 9 42 8.87 0.151 0.092 8.87 Goodacre 4 46 8.79 0.044 0.0368.79 Compound 102

The present disclosure describes these Compounds B and C and variousmethods and compositions relating thereto. Furthermore, the presentdisclosure documents certain surprising and unexpected attributes ofthese compounds, even when compared with structurally similar agents.

Specifically, it has been found that compounds that lack the difluorosubstituted phenyl bridge present in the patent applications presentedby AstraZeneca (PCT Application Publication No. WO 2014/191726) andGenentech (PCT Application Publication No. WO 2016/097072) are potent inblocking estrogen driven gene induction and estrogen driven human breastcancer proliferation, as illustrated above in Table 1 as well as inFIGS. 5A-5B.

As others have noted, particularly in the field of estrogen receptorantagonists, moieties which have been found to enhance antagonistactivity in individual SERMs are not necessarily interchangeable amongstructurally distinct compound cores. For example, as noted by Blizzard,et al., the use of a specific side chain found to increase potency intheir platform was found to have no effect on the potency of otherestrogen receptor antagonists. See Blizzard, et al., “Estrogen receptorligands. Part 14: Application of novel antagonist side chains toexisting platforms,” Bioorganic & Medicinal Chemistry Letters,15:5124-5128 (2005).

The present disclosure further demonstrates that compounds of thepresent invention act as complete antiestrogens (e.g., in that theycompletey block the ability of estrogen to regulate the expression oftarget genes and cellular responses in all cell types, including uterinecells). Those skilled in the art are aware of assays relied upon in thefield to demonstrate or assess degree of antiestrogen activity. Forexample, the well-established rodent uterine weight gain assay (see, forexample, Wakeling et al., 1991, A Potent Specific Pure Antiestrogen withClinical Potential, Cancer Research 51, 3867-3873), is commonly used toassess degree of antiestrogen activity. Also, induction of alkalinephosphatase gene activity in human uterine cells grown in culturecorrelates well with the rodent uterine weight gain assay and can beused as an in vitro assay to distinguish between partial and completeantiestrogens. See U.S. Pat. No. 9,018,244. Those skilled in the art arealso aware that complete antiestrogen activity is typically consideredto be desirable in compounds to be utilized as active pharmaceuticalingredients in drug products. For example, fulvestrant, which iscurrently marketed under the trade name FASLODEX® for treatment ofhormone-receptor-positive metastatic breast cancer in postmenopausalwomen with disease progression following antiestrogen therapy, isheralded as a pure antiestrogen with no intrinsic estrogen-likeproperties based at least in part on its performance in the rodentuterine weight gain assay. (see, for example, Wakeling et al., 1991, APotent Specific Pure Antiestrogen with Clinical Potential, CancerResearch 51, 3867-3873).

By contrast, however, many other compounds reported to have antiestrogencharacter or activity, including those described by AstraZeneca asdiscussed above, and endoxifen, an active metabolite of thewell-established breast cancer drug tamoxifen, show only incompleteantiestrogen activity in standard assays.

Further, Compounds B and C show great potential usefulness in treatinghuman estrogen receptor driven pathologies such as breast cancer, asthey are comparable in activity and function to fulvestrant, which hasbeen shown to be superior to other hormonal therapies for treating firstline metastatic human breast cancer. See PCT Application Publication No.WO2016/097072, page 19, lines 6-9 (noting fulvestrant is used to treatbreast cancer in women which have progressed despite therapy withtamoxifen). Fulvestrant is a selective estrogen receptor degrader (SERD)and a pure antiestrogen with no intrinsic estrogen-like properties.Compounds B and C, similarly, are SERDs (FIGS. 1A-1B) and pureantagonists (FIGS. 6A-6B). Compounds B and C, further, have potencysimilar to fulvestrant in blocking estrogen driven gene expression andproliferation of human breast cancer cells (FIGS. 3 and 4). Compounds Band C are outstandingly potent in shrinking human breast cancerxenografts at the low dose of 10 mg/kg (FIGS. 5A and 5B). Thus compoundsB and C demonstrate usefulness as antiestrogens for treating orpreventing the recurrence or occurrence of breast cancer.

As documented herein, provided compounds show complete antiestrogenactivity in relevant assays, underscoring their usefulness in treatingbreast cancer, and particularly metastatic breast cancer. FIG. 6A-6Bprovides one illustration of this distinction, comparing an examplecompound of the present invention, Compound B, to fluvestrant,endoxifen, AZD9496, and ARN-810 (all compounds pictured in FIG. 6C).

Compounds can be provided if desired as a pharmaceutically acceptablesalt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer,N-oxide and/or substituted derivative optionally in a pharmaceuticallyacceptable composition to treat a disorder that is modulated or affectedby an estrogen receptor, including those treatable with ananti-estrogenic.

The present invention particularly provides two specific compounds,Compound B((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole)and Compound C((1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole),whose structures are surprisingly different from prior compoundsdescribed in the art as being useful estrogen receptor antagonists, andin fact contain specific structural features that teachings in the artaffirmatively indicated were undesirable.

Specifically, Compounds B and C lack the difluorophenyl bridge that ispresent in the most active compounds presented by both AstraZeneca andGenentech. Further, as noted above, Compounds B and C incorporate thespecific unsubstituted phenyl bridge that AstraZeneca indicated wasundesirable due to poor activity as compared to compounds that comprisea difluorophenyl bridge.

It was found, however, that Compounds B and C show comparable activityto fulvestrant, an intramuscularly injected antiestrogen shown to besuperior to other hormonal therapies for treating first-line metastatichuman breast cancer. Compounds B and C have potency similar tofulvestrant in blocking estrogen driven gene expression andproliferation of human breast cancer cells unlike AZD9496. See FIGS. 2and 4.

The present disclosure exemplifies a variety of additional interestingand desirable activities for Compound B. For example, Compound Binhibited E2-induced transcription in breast cells with an IC₅₀=4.35 nM.Compound B also demonstrated inhibition of E2-stimulated proliferationin breast cells with an IC₅₀=4.53 nM. When ECC-1 cells were incubatedwith Compound B, the cells had only 2.18% of the AP activity that thecells would have if AP activity were normalized to the affect that 500pM 17β-estradiol has on ECC-1 cells. When ECC-1 cells were co-treatedwith Compound B and 500 pM 17β-estradiol, the ECC-1 cells exhibited only1.96% of the activity that 17β-estradiol would produce.

As noted above, Compounds B and C are within the scope of Formula I:

wherein:

-   -   X is —CH₂— or —O—;    -   Y is

-   -   R¹, R², R³, and R⁴ are each independently selected from hydrogen        or halo;    -   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalltyl, C₂-C₆alkenyl,        C₀-C₄(C₃-C₆cycloalkyl) or C₁-C₆heteroalkyl;    -   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl or        C₀-C₄(C₃-C₆cycloalkyl);    -   R⁷ and R⁸ are each independently selected from hydrogen or        C₁-C₆alkyl;

or a pharmaceutically acceptable salt or a composition thereof.

The present disclosure defines various useful subgenera within FormulaI. For example, in some embodiments, R¹, R², R³, and R⁴ are eachindependently selected from hydrogen or halo. In some embodiments, R¹,R², R³, and R⁴ are each independently selected from hydrogen or fluoro.In some embodiments, R¹, R², R³, and R⁴ are each hydrogen. As notedabove, for Compounds B and C, R¹, R², R³, and R⁴ are each hydrogen.

In some embodiments, R¹ is hydrogen. In some embodiments, R² ishydrogen. In some embodiments, R³ is hydrogen. In some embodiments, R⁴is hydrogen.

In some embodiments, R¹ is halo. In some embodiments, R² is halo. Insome embodiments, R³ is halo. In some embodiments, R⁴ is halo. In someembodiments, R¹ is fluoro. In some embodiments, R² is fluoro. In someembodiments, R³ is fluoro. In some embodiments, R⁴ is fluoro.

In some embodiments of Formula I, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I, R⁶ is C₁-C₄haloalkyl. In some embodiments ofFormula I, R⁶ is

In some embodiments of Formula I, R⁷ is C₁-C₆alkyl. In some embodimentsof Formula I, R² is methyl.

In some embodiments, a compound is disclosed having Formula I(a):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(a), R¹, R², R³, and R⁴ are eachindependently selected from hydrogen or halo. In some embodiments, R¹,R², R³, and R⁴ are each independently selected from hydrogen or fluoro.In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen.

In other embodiments, R¹ is hydrogen. In other embodiments, R² ishydrogen. In other embodiments, R³ is hydrogen. In other embodiments, R⁴is hydrogen.

In other embodiments, R¹ is halo. In other embodiments, R² is halo. Inother embodiments, R³ is halo. In other embodiments, R⁴ is halo. Inother embodiments, R¹ is fluoro. In other embodiments, R² is fluoro. Inother embodiments, R³ is fluoro. In other embodiments, R⁴ is fluoro. Insome embodiments, only one of R¹, R², R³, and R⁴ is halo (e.g., fluoro).

In some embodiments of Formula I(a), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(a), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(a), R⁶ is

In some embodiments of Formula I(a), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(a), R⁷ is methyl.

In certain embodiments, a compound is disclosed having Formula I(b):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(b), R¹, R², R³, and R⁴ are eachindependently selected from hydrogen or halo. In some embodiments, R¹,R², R³, and R⁴ are each independently selected from hydrogen or fluoro.In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen.

In some embodiments, R¹ is hydrogen. In some embodiments, R² ishydrogen. In some embodiments, R³ is hydrogen. In some embodiments, R⁴is hydrogen.

In some embodiments, R¹ is halo. In some embodiments, R² is halo. Insome embodiments, R³ is halo. In some embodiments, R⁴ is halo. In someembodiments, R¹ is fluoro. In some embodiments, R² is fluoro. In someembodiments, R³ is fluoro. In some embodiments, R⁴ is fluoro. In someembodiments, only one of R¹, R², R³, and R⁴ is halo (e.g., fluoro).

In some embodiments of Formula I(b), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(b), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(b), R⁶ is

In some embodiments of Formula I(b), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(b), R⁷ is methyl.

In certain embodiments, a compound is disclosed having Formula I(c):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(c), R¹, R², R³, and R⁴ are eachindependently selected from hydrogen or halo. In some embodiments, R¹,R², R³, and R⁴ are each independently selected from hydrogen or fluoro.In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen.

In some embodiments, R¹ is hydrogen. In some embodiments, R² ishydrogen. In some embodiments, R³ is hydrogen. In some embodiments, R⁴is hydrogen.

In some embodiments, R¹ is halo. In some embodiments, R² is halo. Inother embodiments, R³ is halo. In some embodiments, R⁴ is halo. In someembodiments, R¹ is fluoro.

In some embodiments, R² is fluoro. In some embodiments, R³ is fluoro. Insome embodiments, R⁴ is fluoro. In some embodiments, only one of R¹, R²,R³, and R⁴ is halo (e.g., fluoro).

In some embodiments of Formula I(c), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(c), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(c), R⁶ is

In some embodiments of Formula I(c), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(c), R⁷ is methyl.

In certain embodiments, a compound is disclosed having Formula I(d):

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(d), R¹, R², R³, and R⁴ are eachindependently selected from hydrogen or halo. In some embodiments, R¹,R², R³, and R⁴ are each independently selected from hydrogen or fluoro.In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen.

In some embodiments, R¹ is hydrogen. In some embodiments, R² ishydrogen. In some embodiments, R³ is hydrogen. In some embodiments, R⁴is hydrogen.

In some embodiments, R¹ is halo. In some embodiments, R² is halo. Insome embodiments, R³ is halo. In some embodiments, R.⁴ is halo. In someembodiments, R¹ is fluoro. In some embodiments, R² is fluoro. In someembodiments, R³ is fluoro. In some embodiments, R⁴ is fluoro. In someembodiments, only one of R¹, R², R³, and R⁴ is halo (e.g., fluoro).

In some embodiments of Formula I(d), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(d), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(d), R⁶ is

In some embodiments of Formula I(d), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(d), R⁷ is methyl.

In some embodiments, the present invention provides a compound offormulae I(e)-I(l):

TABLE 2 Formula No. Formula R¹ R² R³ R⁴ I(e)

— Halo Halo Halo I(f)

Halo Halo — Halo I(g)

— — Halo Halo I(h)

— Halo — Halo I(i)

— Halo Halo — I(j)

— — — Halo I(k)

— Halo — — I(l)

— — — —wherein each of X, Y, R⁶, R⁷ and R⁸ is as defined above and describedherein.

In some embodiments of Formulae I(e), I(f), I(g), I(h), I(i), I(j), I(k)and I(l), halo is fluoro.

In some embodiments, the present invention provides a compound offormula I(j):

wherein

-   -   R⁴ is halo and R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(j), R⁴ is fluoro.

In some embodiments of Formula I(j), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(j), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(j), R⁶ is

In some embodiments of Formula I(j), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(j), R⁷ is methyl.

In some embodiments, the present invention provides a compound offormula I(j)-1:

wherein

-   -   R⁴ is halo and R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(j)-1, R⁴ is fluoro.

In some embodiments of Formula I(j)-1, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(j)-1, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(j)-1, R⁶ is

In some embodiments of Formula I(j)-1, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(j)-1, R⁷ is methyl.

In some embodiments, the present invention provides a compound offormula I(j)-2:

wherein

-   -   R⁴ is halo and R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(j)-2, R⁴ is fluoro.

In some embodiments of Formula I(j)-2, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(j)-2, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(j)-2, R⁶ is

In some embodiments of Formula I(j)-2, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(j)-2, R⁷ is methyl.

In some embodiments, the present invention provides a compound offormula I(j)-3:

wherein

-   -   R⁴ is halo and R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(j)-3, R⁴ is fluoro.

In some embodiments of Formula I(j)-3, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(j)-3, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(j)-3, R⁶ is

In some embodiments of Formula I(j)-3, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(j)-3, R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(j)-4:

wherein

-   -   R⁴ is halo and R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(j)-4, R⁴ is fluoro.

In some embodiments of Formula I(j)-4, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(j)-4, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(j)-4, R⁶ is

In some embodiments of Formula I(j)-4, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(j)-4, R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(l):

wherein

-   -   R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(1), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(l), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(l), R⁶ is

In some embodiments of Formula I(l), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(l), R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(l)-1:

wherein

-   -   R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(l)-1, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(l)-1, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(l)-1, R⁶ is

In some embodiments of Formula I(l)-1, R⁷ i s C₁-C₆alkyl. In someembodiments of Formula I(l)-1, R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(l)-2:

wherein

-   -   R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(l)-2, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(l)-2, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(l)-2, R⁶ is

In some embodiments of Formula I(l)-2, R⁷ i s C₁-C₆alkyl. In someembodiments of Formula I(l)-2, R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(l)-3:

wherein

-   -   R⁵, R⁶, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(l)-3, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(l)-3, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(l)-3, R⁶ is

In some embodiments of Formula I(l)-3, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(l)-3, R⁷ is methyl.

In some embodiments, a compound is disclosed having formula I(l)-4:

wherein

-   -   R⁵, R⁵, R⁷ and R⁸ are as defined above;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula I(l)-4, R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(l)-4, R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(l)-4, R⁶ is

In some embodiments of Formula I(l)-4, R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(l)-4, R⁷ is methyl.

In some embodiments, the present invention provides a compound ofFormula I(m):

wherein

-   -   R⁶, R⁷, and Y are as defined above.

In some embodiments of Formula I(m), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(m), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(m), R⁶ is

In some embodiments of Formula I(m), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(m), R⁷ is methyl.

In some embodiments, the present invention provides a compound ofFormula I(n)

wherein

R⁶, R⁷, and Y are as defined above.

In some embodiments of Formula I(n), R⁶ is C₁-C₆haloalkyl. In someembodiments of Formula I(n), R⁶ is C₁-C₄haloalkyl. In some embodimentsof Formula I(n), R⁶ is

In some embodiments of Formula I(n), R⁷ is C₁-C₆alkyl. In someembodiments of Formula I(n), R⁷ is methyl.

In some embodiments of any of the Formulae described herein (e.g.,Formulae I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j),I(j)-1, I(j)-2, I(j)-3, I(k), I(l), I(l)-1, I(l)-3, I(l)-4, I(m), andI(n)), R⁵ is C₁-C₆alkyl. In some embodiments of any of the Formulaedescribed herein, R³ is C₁-C₅alkyl. In some embodiments of any of theFormulae described herein, R⁵ is C₁-C₄alkyl. In some embodiments of anyof the Formulae described herein, R⁵ is C₁-C₃alkyl. In some embodimentsof any of the Formulae described herein, R⁵ is C₁-C₂alkyl. In someembodiments of any of the Formulae described herein, R⁵ is chosen frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, pentyl, isopentyl, neopentyl, or hexyl. In some embodimentsof any of the Formulae described herein, R⁵ is methyl. In someembodiments of any of the Formulae described herein, R⁵ is ethyl. Insome embodiments of any of the Formulae described herein, R⁵ is propyl.

In some embodiments of any of the Formulae descibred herein, R⁵ isC₁-C₆haloalkyl. In some embodiments of any of the Formulae describedherein, R⁵ is —CH₂F. In some embodiments of any of the Formulaedescribed herein, R⁵ is —CHF₂. In some embodiments of any of theFormulae described herein, R⁵ is —CF₃.

In some embodiments of any of the Formulae described herein, R⁶ isselected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl orC₀-C₄(C₃-C₆cycloalkyl). In some embodiments of any of the Formulaedescribed herein, R⁶ is C₁-C₆haloalkyl. In some embodiments of any ofthe Formulae described herein, R⁶ is —CH₂CF(CH₃)₂. In some embodimentsof any of the Formulae described herein, R⁶ is C₁-C₅alkyl or haloalkyl.In some embodiments of any of the Formulae described herein, R⁶ isC₁-C₄alkyl or haloalkyl. In some embodiments of any of the Formulaedescribed herein, R⁶ is C₁-C₃alkyl or haloalkyl. In some embodiments ofany of the Formulae described herein, R⁶ is C₁-C₂alkyl. In someembodiments of any of the Formulae described herein, R⁶ is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, pentyl, isopentyl, neopentyl, or hexyl. In some embodimentsof any of the Formulae described herein, R⁶ is methyl or halomethyl. Insome embodiments of any of the Formulae described herein, R⁶ is ethyl orhaloethyl.

In some embodiments of any of the Formulae described herein, R⁷ and R⁸are each independently selected from hydrogen or C₁-C₆alkyl (which canbe in any subembodiment as described above for R⁵ or R⁶). In someembodiments of any of the Formulae described herein, R⁷ is methyl and R⁸is hydrogen.

Moreover, the present disclosure reports Compound B((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole):

Further, the present disclosure reports Compound C((1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethypazetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole):

Terminology

The foregoing general description and the following detailed descriptionare exemplary and explanatory only and are not restrictive of theinvention. Other features and benefits of any one or more of theembodiments will be apparent from the following detailed description,and from the claims.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In case of conflict, thepresent specification, including definitions, will control. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments of the presentinvention, suitable methods and materials are described below. Inaddition, the materials, methods, and examples are illustrative only andnot intended to be limiting.

When an amount, concentration, or other value or parameter is given aseither a range, preferred range or a list of upper preferable valuesand/or lower preferable values, this is to be understood as specificallydisclosing all ranges formed from any pair of any upper range limit orpreferred value and any lower range limit or preferred value, regardlessof whether ranges are separately disclosed. Where a range of numericalvalues is recited herein, unless otherwise stated, the range is intendedto include the endpoints thereof, and all integers and fractions withinthe range.

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having” or any other variation thereof, areintended to cover a non-exclusive inclusion. For example, a process,method, article, or apparatus that comprises a list of elements is notnecessarily limited to only those elements but may include otherelements not expressly listed or inherent to such process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). Unless otherwise stated,the invention encompasses compounds described herein as individualisomers substantially free of other isomers, and alternatively, asmixtures of various isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group that in one embodiment has from 1 to 6 carbon atoms(“C₃₋₆alkyl”). In some embodiments, an alkyl group has 1 to 5 carbonatoms (“C₁₋₅alkyl”). In some embodiments, an alkyl group has 1 to 4carbon atoms (“C₁₋₄alkyl”). In some embodiments, an alkyl group has 1 to3 carbon atoms (“C₁₋₃alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂alkyl”). In some embodiments, an alkyl group has1 carbon atom (“C₁alkyl”). In some embodiments, an alkyl group has 2 to6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), amyl(C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), andn-hexyl (C₆). Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents, e.g., for instance from 1 to 5 substituents, 1 to3 substituents, or 1 substituent. In certain embodiments, the alkylgroup is unsubstituted C₁₋₆ alkyl (e.g., —CH₃). In certain embodiments,the alkyl group is substituted C₁₋₆ alkyl.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group that in one embodiment has from 2 to 6 carbon atoms,one or more carbon-carbon double bonds, and no triple bonds(“C₂₋₆alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbonatoms (“C₂₋₅alkenyl”). In some embodiments, an alkenyl group has 2 to 4carbon atoms (“C₂₋₄alkenyl”). In some embodiments, an alkenyl group has2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenylgroup has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon-carbondouble bonds can be internal (such as in 2-butenyl) or terminal (such asin 1-butenyl). Examples of C₂₋₄ alkenyl groups include ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), and the like. Examples of C₂₋₆ alkenyl groups includethe aforementioned C₂₋₄ alkenyl groups as well as pentenyl (C₅),pentadienyl (C₅), hexenyl (C₆), and the like. Unless otherwisespecified, each instance of an alkenyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkenyl”) orsubstituted (a “substituted alkenyl”) with one or more substituentse.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkenyl group is unsubstitutedC₂₋₆ alkenyl. In certain embodiments, the alkenyl group is substitutedC₂₋₆ alkenyl.

“Carbocyclyl”, “cycloalkyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 8 ring carbonatoms (“C₃₋₈carbocyclyl”) and zero heteroatoms in the non-aromatic ringsystem. Exemplary C₃₋₆ carbocyclyl groups include, without limitation,cyclopropyl (C₃), cyclopropenyl (C₃, cyclobutyl (C₄), cyclobutenyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈ carbocyclylgroups include, without limitation, the aforementioned C₃₋₆ carbocyclylgroups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl(C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈),bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like.As the foregoing examples illustrate, in certain embodiments, thecarbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) orcontains a fused, bridged or spiro ring system such as a bicyclic system(“bicyclic carbocyclyl”) and can be saturated or can be partiallyunsaturated. Unless otherwise specified, each instance of a carbocyclylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a “substitutedcarbocyclyl”) with one or more substituents. In certain embodiments, thecarbocyclyl group is unsubstituted C₃₋₈ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₈ carbocyclyl.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br) or iodine (iodo, —I).

“Haloalkyl” is a substituted C₁-C₆alkyl group as defined herein whereinone or more of the hydrogen atoms of the C₁-C₆alkyl group areindependently replaced by a halogen, e.g., fluoro, bromo, chloro, oriodo. In some embodiments, the alkyl moiety has 1 to 6 carbon atoms(“C₁-C₆alkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbonatoms ('C₁-C₄haloalkyl″). In some embodiments, the alkyl moiety has 1 to3 carbon atoms (“C₁-C₃haloalkyl”). In some embodiments, the alkyl moietyhas 1 to 2 carbon atoms (“C₁-C₂haloalkyl”). In some embodiments, thealkyl moiety has 1 carbon atom (“C₁haloalkyl”). In some embodiments, allof the hydrogen atoms are replaced with fluoro. Examples of haloalkylgroups include CH₂F, CHF₂, —,CF₃, —CH₂CH₂F, CH₂CHF₂, —CH₂CF₃ and thelike.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl and the like having from 1 to 3, and typicallyone heteroatom.

“Heterocyclyl,” “heterocycle” or “heterocyclic” refers to a radical of a3- to 6-membered nonaromatic ring system having ring carbon atoms and 1to 2 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“3-6 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or a fused, bridged or spiro ring system and can be saturated or can bepartially unsaturated. Heterocyclyl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heterocyclyl” alsoincludes ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more carbocyclyl groups wherein the point ofattachment is either on the carbocyclyl or heterocyclyl ring. Unlessotherwise specified, each instance of heterocyclyl is independentlyunsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-6 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-6 membered heterocyclyl. In one embodiment, theheterocyclyl group is substituted 4-membered heterocyclyl. In oneembodiment, the heterocyclyl group is substituted azetidine.

Alkyl, alkenyl, carbocyclyl, heteroalkyl and heterocyclyl groups, asdefined herein, are optionally substituted (e.g., “substituted” or“unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heteroalkyl). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety. Exemplary carbon and nitrogen atomsubstituents include, but are not limited to, halogen, hydroxyl, amino,cyano, —COOH, —CONH₂, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkoxy, C₂-C₆acyl,C₁-C₆alkylester, (mono- and di-C₁-C₆alkylamino)C₀-C₂alkyl-,C₁-C₄haloalkyl, and C₁-C₄haloalkoxy.

“Agent” or “anti-cancer agent,” as used herein, refers tochemotherapeutic agents, targeted therapies, and hormonal therapies.Suitable examples of anti-cancer agents are, for example, thechemotherapy agent gemcitibine, the targeted therapies palbocilib andeverolimus, and the hormonal therapies for breast cancer such astamoxifen, fulvestrant, steroidal aromatase inhibitors, andnon-steroidal aromatase inhibitors.

Purity and Stereochemistry of Compounds

As used herein the term “enantiomerically pure” or “pure enantiomer”denotes that the compound comprises at least 95% by weight of a singleenantiomer. In alternative embodiments, when specified, the term mayrefer to at least 96% by weight, at least 97% by weight, at least 98% byweight, at least 98.5% by weight, at least 99% by weight, at least 99.2%by weight, at least 99.5% by weight, at least 99.6% by weight, at least99.7% by weight, at least 99.8% by weight or at least 99.9% by weight,of the enantiomer. The weights are based upon total weight of allenantiomers or stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure (1R,3R) compound” refers to at least 95% byweight (1R,3R)-compound and at most about 5% by weight of the (1S,3R),(1R,3S), and (1S,3S) compounds. In alternative embodiments, whenspecified, the term can refer to at least about 99% by weight(1R,3R)-compound and at most about 1% by weight of the (1S,3R), (1R,3S),and (1S,3S) compounds or at least about 99.9% by weight (1R,3R)-compoundor at most about 0.1% by weight of the (1S,3R), (1R,3S), and (1S,3S)compounds. In certain embodiments, the weights are based upon totalweight of compound.

As used herein the term “diastereomerically pure” or “pure diastereomer”denotes that the compound in the specific diastereomer, comprisesapproximately 95% or more by weight. In alternative embodiments, theterm may refer to more than 96% by weight, more than 97% by weight, morethan 98% by weight, more than 98.5% by weight, more than 99% by weight,more than 99.2% by weight, more than 99.5% by weight, more than 99.6% byweight, more than 99.7% by weight, more than 99.8% by weight or morethan 99.9% by weight of the diastereomer. The weights are based upontotal weight of all stereoisomers of the compound.

In one embodiment, the compounds are provided generally in any state ofpurity. In another embodiment, the compounds of the Formulas aresubstantially pure. By use of the term “substantially pure”, it is meantthat the compounds of Formula I are at least about 80% by weight pure.In another embodiment, the compounds of Formula I are at least about 85%by weight pure, while in another embodiment, it is at least about 90% byweight pure. In still another embodiment, the term “substantially pure”means that the compounds of Formula I are at least about 95% pure byweight. In another embodiment, it is at least about 97% pure by weight,and in another embodiment, it is at least about 98% and in still anotherembodiment, it is at least about 99% pure by weight. Unless otherwiseindicated, the term substantially pure means at least about 90% byweight. The compounds of Formula I include stereoisomers thereof,including, without limitation, enantiomers, diastereomers and racemicmixtures thereof, unless the chemical structure depicts a certain stereoconfiguration. In that case, the corresponding enantiomer, diastereomeror racemic mixture may be used in an alternative embodiment.

In particular, it is noted that the carbon atoms at the 1 and3-positions of the tetrahydro-1H-pyrido[3,4-b]indole core of thecompounds of Formula I which are bonded to a phenyl group; and R⁷ and R⁸groups respectively, are chiral carbons; thus, the compounds may existin either the R or S configuration at these positions. The presentdisclosure includes all of the possible stereoisomers at the 1 and3-positions of the tetrahydro-1H-pyrido[3,4-b]indole, or a mixturethereof in any ratio, including a racemic mixture. In one embodiment,the carbon atoms at the 1 and 3-positions of thetetrahydro-1H-pyrido[3,4-b]indole bonded to a phenyl group; and R⁷ andR⁸ groups respectively have the (1R,3R) configuration. In anotherembodiment, the carbon atoms at the 1 and 3-positions of thetetrahydro-1H-pyrido[3,4-b]indole bonded to a phenyl group; and R⁷ andR⁸ groups respectively have the (1S,3S) configuration. In anotherembodiment, the carbon atoms at the 1 and 3-positions of thetetrahydro-1H-pyrido[3,4-b]indole bonded to a phenyl group; and R⁷ andR⁸ groups respectively have the (1R,3S) configuration. In anotherembodiment, the carbon atoms at the 1 and 3-positions of thetetrahydro-1H-pyrido[3,4-b]indole bonded to a phenyl group; and R⁷ andR⁸ groups respectively have the (1S,3R) configuration.

Compounds of the present disclosure include diastereomerically orenantiomerically pure compounds of Formula I. These diastereomericallyor enantiomerically pure compounds of Formula I provided herein may beprepared according to techniques known to those of skill in the art. Forinstance, they may be prepared by chiral or asymmetric synthesis from asuitable optically pure precursor or obtained from a racemate or mixtureof enantiomers or diastereomers by any conventional technique, forexample, by chromatographic resolution using a chiral column, TLC or bythe preparation of diastereoisomers, separation thereof and regenerationof the desired enantiomer or diastereomer. See, e.g., “Enantiomers,Racemates and Resolutions,” by J. Jacques, A. Collet, and S. H. Wilen,(Wiley-Interscience, New York, 1981); S. H. Wilen, A. Collet, and J.Jacques, Tetrahedron, 2725 (1977); E. L. Eliel Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and S. H. Wilen Tables of ResolvingAgents and Optical Resolutions 268 (E. L. Eliel ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972, Stereochemistry of Organic Compounds,Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley &Sons, Inc.), and Stereoselective Synthesis A Practical Approach, MihályNógrádi (1995 VCH Publishers, Inc., NY, N.Y.).

In certain embodiments, a diastereomerically pure compound of Formula Imay be obtained by reaction of the racemate or mix of diastereomers witha suitable optically active acid or base. Suitable acids or basesinclude those described in Bighley et al., 1995, Salt Forms of Drugs andAdsorption, in Encyclopedia of Pharmaceutical Technology, vol. 13,Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H.Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher,1973, J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolutionvia Diastereomeric Salt Formation, the contents of which are herebyincorporated by reference in their entireties.

Enantiomerically or diastereomerically pure compounds can also berecovered either from the crystallized diastereomer or from the motherliquor, depending on the solubility properties of the particular acidresolving agent employed and the particular amine enantiomer ordiastereomer used. The identity and optical purity of the particularcompound so recovered can be determined by polarimetry or otheranalytical methods known in the art. The diastereoisomers can then beseparated, for example, by chromatography or fractional crystallization,and the desired enantiomer or diastereomer regenerated by treatment withan appropriate base or acid. The other enantiomer or diastereomer may beobtained from the racemate or mix of diastereomers in a similar manneror worked up from the liquors of the first separation.

In certain embodiments, an enantiomerically or diastereomerically purecompound can be separated from racemic compound or a mixture ofdiastereomers by chiral chromatography. Various chiral columns andeluents for use in the separation of the enantiomers or diastereomersare available and suitable conditions for the separation can beempirically determined by methods known to one of skill in the art.Exemplary chiral columns available for use in the separation of theenantiomers provided herein include, but are not limited to, CHIRALPAK®IA-3, CHIRALPACK® IC, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD,CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ andCHIRALCEL® OK.

Isotopic Substitution

The present invention includes the compounds of Formula I and the use ofcompounds with desired isotopic substitutions of atoms, at an amountabove the natural abundance of the isotope, i.e., enriched. Isotopes areatoms having the same atomic number but different mass numbers, i.e.,the same number of protons but a different number of neutrons. By way ofgeneral example and without limitation, isotopes of hydrogen, forexample, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures. Alternatively or in addition, isotopes of carbon,e.g., ¹³C and ¹⁴C, may be used. A preferred isotopic substitution isdeuterium for hydrogen at one or more locations on the molecule toimprove the performance of the drug. The deuterium can be bound in alocation of bond breakage during metabolism (an α-deuterium kineticisotope effect) or next to or near the site of bond breakage (aβ-deuterium kinetic isotope effect).

Substitution with isotopes such as deuterium can afford certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements. Substitution of deuterium for hydrogen at a site ofmetabolic break down can reduce the rate of or eliminate the metabolismat that bond. At any position of the compound that a hydrogen atom canbe present, the hydrogen atom can be any isotope of hydrogen, includingprotium (¹H), deuterium (²H) and tritium (³H). Thus, reference herein toa compound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

The term “isotopically-labeled” analog refers to an analog that is a“deuterated analog”, a “¹³C-labeled analog,” or a“deuterated/¹³C-labeled analog.” The term “deuterated analog” means acompound described herein, whereby an H-isotope, i.e., hydrogen/protium(¹H), is replaced by an H-isotope, i.e., deuterium (²H). Deuteriumsubstitution can be partial or complete. Partial deuterium substitutionmeans that at least one hydrogen is substituted by at least onedeuterium. In certain embodiments, the isotope is 90, 95 or 99% or moreenriched in an isotope at any location of interest. In some embodimentsit is deuterium that is 90, 95 or 99% enriched at a desired location. Incertain embodiments, deuterium in place of a hydrogen at one or more ofthe positions of Formula I are provided.

Compounds of Formula I

In one embodiment, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

In one embodiment, a compound of Formula I is provided as a prodrug, forexample, a methyl dihydrogen phosphate, see, US 2012/0238755.

In some embodiments, the present invention provides a compound:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound:

or a pharmaceutically acceptable salt thereof.

Compounds of the present invention provide surprising advantages overthe compounds reported by AstraZeneca (PCT Application Publication No.WO 2014/191726) and Genentech (PCT Application Publication No. WO2016/097072) in that they lack the difluorophenyl bridge found in almostall compounds reported by AstraZeneca and Genetech, yet provide improvedbiological activity as inhibitors of the estrogen receptor over thecompounds reported by either AstraZeneca or Genentech, as discussedabove and illustrated further in the Examples below.

Pharmaceutical Compositions

A “dosage form” means a unit of administration of an active agent.Non-limiting examples of dosage forms include tablets, capsules,injections, suspensions, liquids, intravenous fluids, emulsions, creams,ointments, suppositories, inhalable forms, transdermal forms, and thelike.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, such as a compound or salt of one of the active compoundsdisclosed herein, and at least one other substance, such as a carrier.Pharmaceutical compositions optionally contain more than one activeagents. “Pharmaceutical combinations” or “combination therapy” refers tothe administration of at least two active agents, and in one embodiment,three or four or more active agents which may be combined in a singledosage form or provided together in separate dosage forms optionallywith instructions that the active agents are to be used together totreat a disorder as described herein.

The compounds of the invention can be administered in an effectiveamount in a pharmaceutical composition and dosage form suitable for oraldelivery to the patient, typically a human for any of the conditionsdescribed herein. Alternatively, the compounds can be delivered in acarrier suitable for topical, transdermal (including by patch),intravenous, intra-arterial, vaginal, rectal, buccal, sublingual,parenteral, intraaortal, subcutaneous or other desired delivery route,including any method of controlled delivery, for example, usingdegradable polymers, or with nano or microparticles, liposomes, layeredtablets or other structural frameworks which slow delivery.

In one aspect, the active compound of the invention can be used toprevent a disorder modulated through the estrogen receptor, whichcomprises administering to a patient in need of such prevention, aprophylactically effective amount of a compound or pharmaceuticalcomposition.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts have low toxicity and may be inorganic or organic acidaddition salts and base addition salts. Specifically, such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of nontoxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. A counterion oranionic counterion can be used in a quaternary amine to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, and the like), and carboxylateions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate,lactate, tartrate, glycolate, and the like).

“Pharmaceutically acceptable carrier” refers to a diluent, adjuvant,excipient or other carrier in which a compound of the invention isadministered.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, is sufficiently non-toxic, and neither biologically norotherwise undesirable. A “pharmaceutically acceptable excipient” as usedin the present application includes both one and more than one suchexcipient.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsthat are useful to treat any of the disorders described herein, or tocontrol or improve the underlying cause or symptoms associated with anyphysiological or pathological disorder described herein in a host,typically a human. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Nonlimiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups.

“Solvate” refers to forms of the compound that are associated with asolvent or water (also referred to as “hydrate”), usually by asolvolysis reaction. This physical association can include hydrogenbonding. Conventional solvents include water, ethanol, acetic acid andthe like. The compounds of the invention may be prepared e.g. incrystalline or liquid form and may be solvated or hydrated. Suitablesolvates include pharmaceutically acceptable solvates, such as hydrates,and further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

A “host” or “subject” to which administration is contemplated includesany host that responds to anti-estrogenic therapy or therapy thatmodulates estrogen receptor activity and is typically a human (i.e., afemale or male of any age group, e.g., a pediatric subject (e.g.,infant, child, adolescent)) or adult subject (e.g., young adult,middle-aged adult or senior adult)). In an alternative embodiment, thehost is a non-human animal, e.g., a mammal such as primates (e.g.,cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats,rodents, cats, and/or dogs.

In some embodiments, the pharmaceutical composition is a tablet, a pill,a capsule, a liquid, a suspension, a gel, a dispersion, a suspension, asolution, an emulsion, an ointment, or a lotion.

Effective amounts of a compound of Formula I or its pharmaceuticallyacceptable salt etc., in the composition will typically be determined bya physician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, thecompound or salt administered, the age, weight, and response of theindividual patient, the severity of the patient's symptoms, and thelike.

For oral dosing, any dose is appropriate that achieves the desiredgoals. In one example, suitable daily dosages are between about0.1-4,000 mg, more typically between 5 mg and 1 gram, more typicallybetween 10 mg and 500 mg, and administered orally once-daily,twice-daily or three times-daily, continuous (every day) orintermittently (e.g., 3-5 days a week). For example, when used to treatany disorder described herein, the dose of the compounds of Formula I ortheir pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, rotamer or tautomer is provided in a dosage of at leastabout 0.1, 0.5, 1, 5, 25, 50, 75, 100, 150, 200, 300, 400, 500, 600,700, 800,1000, 1200, 1500 or 2000 mg per day. In one embodiment, thedose of the compounds of Formula I or their pharmaceutically acceptablesalt, solvate, hydrate, prodrug, stereoisomer, rotamer or tautomer isprovided in a dosage of at least about 10, 50, 100, 200, 250, 1,000 orup to about 2,000 mg per day. Alternatively, nonlimiting dosages canrange from about 0.01 to about 20 mg/kg of the compound of Formula I orits pharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer or tautomer provided herein, with typical doses providingfrom about 0.1 to about 10 mg/kg and especially about 1 to about 5mg/kg.

Described herein below are various nonlimiting examples ofpharmaceutically acceptable compositions that include a compound ofFormula I or its pharmaceutically acceptable salt, etc., in apharmaceutically acceptable carrier. The formulation includes the activeingredient, either as a weight ratio or as a weight amount. It is to beunderstood, unless indicated to the contrary, that the weight amount andweight ratios are based upon the molecular weight of the compound ofFormula I, even if the formulation contains the salt form thereof.

Compositions for oral administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. Typically, the compositionsare presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material of the compoundof Formula I or its pharmaceutically acceptable salt calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include prefilled,premeasured ampules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the compound of Formula I or its pharmaceuticallyacceptable salt may be present as a minor component (as a nonlimitingexample, from about 0.1 to about 50% by weight or preferably from about1 to about 40% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions comprised of a compound of Formula I or itspharmaceutically acceptable salts are contemplated within the presentdisclosure. These injectable solutions use injectable carriers knownwithin the art, such as injectable sterile saline or phosphate-bufferedsaline carriers and the like.

Injection dose levels of injectable solutions comprised of compounds ofFormula I or their pharmaceutically acceptable salts are provided in anydesired dosage, for example, from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. In one embodiment, a preloading bolus of from about 0.1 mg/kgto about 10 mg/kg or more comprised of the compounds of Formula I ortheir pharmaceutically acceptable salts may also be administered toachieve adequate steady state levels. The maximum total dose is notexpected to exceed about 2-5 g/day for a 40 to 80 kg human patient.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses. Transdermalcompositions are typically formulated as a topical ointment or creamcontaining the compound of Formula I or its pharmaceutically acceptablesalt, for example in an amount ranging from about 0.01 to about 20% byweight, in another embodiment, from about 0.1 to about 20% by weight, instill another embodiment, from about 0.1 to about 10% by weight, and instill a different embodiment from about 0.5 to about 15% by weight. Whenformulated as an ointment, the compound of Formula I or itspharmaceutically acceptable salt will typically be combined with eithera suitable delivery polymeric composition, or a paraffinic or awater-miscible ointment base. Alternatively, the compound of Formula Ior its pharmaceutically acceptable salt may be formulated in a creamwith, for example an oil-in-water cream base. Such transdermalformulations are well-known in the art and generally include additionalingredients to enhance the dermal penetration of stability of the activeingredients or the formulation. All such known transdermal formulationsand ingredients are included within the scope provided herein.

The compound of Formula I or its pharmaceutically acceptable salt can beadministered by a transdermal device. Transdermal administration can beaccomplished using a patch either of the reservoir or porous membranetype, or of a solid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compound of Formula I or its pharmaceutically acceptable salt canalso be administered in sustained release forms or from sustainedrelease drug delivery systems. A description of representative sustainedrelease materials can be found in Remington's Pharmaceutical Sciences.

In certain embodiments, the formulation comprises water. In anotherembodiment, the formulation comprises a cyclodextrin derivative. Incrtain embodiments, the formulation comprises hexapropyl-β-cyclodextrin.In a more particular embodiment, the formulation compriseshexapropyl-β-cyclodextrin (10-50% in water). In a more particularembodiment, the formulation comprises Captisol®.

The following formulation examples illustrate non-limitingrepresentative pharmaceutical compositions that may be prepared inaccordance with this disclosure for the purpose of illustration only.The present invention is specifically not limited to the followingpharmaceutical compositions. Although the examples in the formulationsherein refer to compounds of Formula I it is understood that thepharmaceutically acceptable salt, solvate, hydrate, prodrug,stereoisomer, tautomer, rotamer, N-oxide and/or substituted derivativesalt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer,N-oxide and/or substituted derivative thereof may be used in theirstead. Thus, for example, if the compound of Formula I is present in theformulation as its salt, the weight ratio is to be based upon the weightof the compound of Formula I present in the formulation without takinginto account the weight attributable to the salt thereof.

Formulation 1—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into240-270 mg tablets (80-90 mg of a compound of Formula I per tablet) in atablet press.

Formulation 2—Capsules

A compound of Formula I may be admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of a compound of Formula I per capsule).

Formulation 3—Liquid

A compound of Formula I (125 mg) may be admixed with sucrose (1.75 g)and xanthan gum (4 mg) and the resultant mixture may be blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, andcolor are diluted with water and added with stirring. Sufficient watermay then be added to produce a total volume of 5 mL.

Formulation 4—Tablets

A compound of Formula I can be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of a compound of Formula I) in a tabletpress. In other embodiments, there is between 10 and 500 mg of acompound of Formula I in the oral tablet.

Formulation 5—Injection

A compound of Formula I can be dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5, or 10, or 15, or 20, or 30 or 50 mg/mL.

Formulation 6—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into90-150 mg tablets (30-50 mg of a compound of Formula I per tablet) in atablet press.

Formulation 7—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into30-90 mg tablets (10-30 mg of a compound of Formula I per tablet) in atablet press.

Formulation 8—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into0.3-30 mg tablets (0.1-10 mg of a compound of Formula I per tablet) in atablet press.

Formulation 9—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into150-240 mg tablets (50-80 mg of a compound of Formula I per tablet) in atablet press.

Formulation 10—Tablets

A compound of Formula I may be admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed intotablets (5-1000 mg of a compound of Formula I per tablet) in a tabletpress.

Methods of Use in Medical Therapy

A compound of Formula I described herein or its salt or derivative asdescribed herein or a pharmaceutically acceptable composition thereofhas anti-estrogenic activity useful to treat any disorder modulated,mediated or affected by the estrogen receptor or as otherwise describedherein. Nonlimiting examples of disorders are estrogen and/orprogesterone negative or positive breast cancer, ovarian, endometrial,vaginal cancer, endometriosis, lung cancer, bone cancer, colorectalendometrial cancer, prostate cancer, uterine cancer and an estrogenreceptor-α dysfunction associated with cancer. They can be used in thetreatment of lung and bronchial cancers that express estrogen receptors.

Compounds descrbed herein can also be used as adjunctive therapy orcombination therapy with another active agent. For example, atherapeutically effective amount of the compound can be used incombination with another anti-cancer agent, especially for estrogenreceptor positive breast cancer, but in some embodiments, for estrogenreceptor negative breast cancer.

In some embodiments, compounds of Formula I or pharmaceuticallyacceptable salts thereof are used in combination or alternation withanother anti-cancer agent for the treatment of cancer, as described morefully herein. In some embodiments, compounds of Formula I or itspharmaceutically acceptable salts thereof are used in combination oralternation with estrogen or a partial estrogen receptor antagonist forthe treatment of a postmenopausal disorder.

In some embodiments, a compound of Formula I or its pharmaceuticallyacceptable salt is used to treat local, advanced or metastatic breastcancer that is positive for expression of estrogen receptors,progesterone receptors or both (receptor positive advanced breastcancer). In an alternative embodiment, the compound of Formula I or itspharmaceutically acceptable salt is used to treat estrogen orprogesterone receptor negative breast cancer. A compound of Formula I orits pharmaceutically acceptable salt can be used as the initialtreatment of advanced breast cancer in patients who have never receivedprevious hormonal therapy for advanced breast cancer, either by itselfor in combination with one or more other anti-cancer agents or otherwiseknown to those skilled in the art. It is also useful for second linetherapy for treatment after a previous anti-hormonal therapy has failed,either by itself or in combination with another anticancer agent, forexample, a targeted therapy such as an mTOR inhibitor such aseverolimus, or a CDK4/6 inhibitor such as palbociclib, abemaciclib, orribociclib.

Compounds of Formula I or their pharmaceutically acceptable salts arealso useful as adjunctive therapy after or instead of chemotherapy,radiation or surgery. Such adjuvant use is often used for several years,perhaps up to 5 years or more, after chemotherapy or other therapieshave been concluded, but may optimally be continued for additionalyears.

Compounds of Formula I or their pharmaceutically acceptable salts arealso useful for the prevention of breast cancer in women at high riskand can be taken for any desired time period, including indefinitely.For example, a patient, typically a woman, with a family history ofbreast cancer, or who has been determined to carry a mutation in theBRACA1 or BRACA2 gene or other genes that predispose a patient to breastcancer may choose to use such preventative treatment instead of amastectomy or other intervention. The compounds of Formula I or theirpharmaceutically acceptable salts described herein are also useful asneoadjuvants to shrink large tumors prior to surgical removal, both toenable breast conservative surgery and to reduce the risk of recurrence.

Selective estrogen receptor modulators (SERMs) such as tamoxifen,raloxifene, lasofoxifene, and bazedoxifene additionally have applicationas hormone replacement therapy to prevent osteoporosis and otherdisorders such as hot flashes, etc. in post-menopausal women, a use thatdepends on their partial estrogen like action, for example, on bone. Thecompound of Formula I or its pharmaceutically acceptable salts describedherein can be employed in combination with an estrogen or a selectiveestrogen receptor modulator to block the unwanted estrogenic activity ofthe therapy. The complete anti-estrogen is dosed in the amount toprevent the adverse action of the estrogen or estrogen receptormodulator on the uterus and mammary gland yet allowing the beneficialaction of estrogen on bone and vasomotor symptoms.

Compounds of Formula I or their pharmaceutically acceptable salts can beadministered for the treatment of cancer, and in particular breastcancer in combination or association with Herceptin, Tykerb, a CDK4/6inhibitor such as palbociclib (originally known as PD-0332991),abemaciclib, ribociclib, an mTOR inhibitor such as Novartis' everolimusand other rapamycin analogs such rapamycin and temsirolimus,Millennium's MLN0128 TORC1/2 inhibitor, an EFGR-family inhibitor such astrastuzumab, pertuzumab, ado-trastuzumab emtansine, erlotinib,gefitinib, neratinib and similar compounds, a PI3 Kinase Inhibitor suchas perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145, ahistone deacetylase inhibitor such as vorinostat, romidepsin,panobinostat, valproic acid, etinostat, and belinostat.

In some embodiments, compounds of any of the Formulae described hereincan be administered in combination with targeted anti-cancer immunetherapies including PD-1 inhibitors such as nivolumab, pembrolizumab,pidilizumab, or BMS 936559, and/or PD-L1 inhibitors such asatezolizumab, avelumab, or durvalumab.

In another method of treatment aspect, provided herein is a method oftreating a mammal susceptible to or afflicted with a conditioninfluenced by estrogen receptor by administering to a subject in needthereof a compound of Formula I or its pharmaceutically acceptable saltthereof.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agents that canmodulate other critical pathways in breast cancer, including but notlimited to those that target IGF1R, EGFR, erB-B2 and 3 the PI3K/AKT/mTORaxis, HSP90, PARD or histone deacetylases.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agents used totreat breast cancer, including but not limited to aromatase inhibitors,anthracyclines, platins, nitrogen mustard alkylating agents, andtaxanes. I(l)lustrative agents used to treat breast cancer, include, butare not limited to, paclitaxel, anastrozole, exemestane,cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine,trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel,toremifene, vinorelbine, capecitabine, ixabepilone, as well as othersdescribed herein.

Generally, ER-related diseases or conditions include ER-α dysfunction isassociated with cancer (bone cancer, breast cancer, lung cancer,colorectal cancer, endometrial cancer, prostate cancer, ovarian anduterine cancer), central nervous system (CNS) defects (alcoholism,migraine), cardiovascular system defects (aortic aneurysm,susceptibility to myocardial infarction, aortic valve sclerosis,cardiovascular disease, coronary artery disease, hypertension),hematological system defects (deep vein thrombosis), immune andinflammation diseases (Graves' Disease, arthritis, multiple sclerosis,cirrhosis), susceptibility to infection (hepatitis B, chronic liverdisease), metabolic defects (bone density, cholestasis, hypospadias,obesity, osteoarthritis, osteopenia, osteoporosis), neurological defects(Alzheimer's disease, Parkinson's disease, migraine, vertigo),psychiatric defects (anorexia nervosa, attention deficit hyperactivitydisorder (ADHD), dementia, major depressive disorder, psychosis) andreproductive defects (age of menarche, endometriosis, infertility.

In some embodiments, compounds disclosed herein are used in thetreatment of an estrogen receptor dependent or estrogen receptormediated disease or condition in a mammal.

In some embodiments, the estrogen receptor dependent or estrogenreceptor mediated disease or condition is selected from cancer, centralnervous system (CNS) defects, cardiovascular system defects,hematological system defects, immune and inflammation diseases,susceptibility to infection, metabolic defects, neurological defects,psychiatric defects and reproductive defects.

In some embodiments, the estrogen receptor dependent or estrogenreceptor mediated disease or condition is selected from bone cancer,breast cancer, lung cancer, colorectal cancer, endometrial cancer,prostate cancer, ovarian cancer, uterine cancer, alcoholism, migraine,aortic aneurysm, susceptibility to myocardial infarction, aortic valvesclerosis, cardiovascular disease, coronary artery disease,hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiplesclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density,cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis, Alzheimer's disease, Parkinson's disease, migraine,vertigo, anorexia nervosa, attention deficit hyperactivity disorder(ADHD), dementia, major depressive disorder, psychosis, age of menarche,endometriosis, and infertility.

In some embodiments, the cancer is an estrogen-sensitive cancer or anestrogen receptor dependent cancer that is resistant to anti-hormonaltreatment. In some embodiments, anti-hormonal treatment includestreatment with at least one agent selected from tamoxifen, fulvestrant,steroidal aromatase inhibitors, and non-steroidal aromataseinhibitors-resistant.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, methods of treatment with compounds describedherein include a treatment regimen that includes administering radiationtherapy to the mammal.

In some embodiments, methods of treatment with compounds describedherein include administering the compound prior to or following surgery.

In some embodiments, methods of treatment with compounds describedherein include administering to the mammal at least one additionalanti-cancer agent.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is chemotherapy-naive.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is being treated for cancer with atleast one anti-cancer agent.

In one embodiment, the cancer is a hormone refractory cancer.

Accordingly, in some embodiments, the present invention provides acompound of Formula I:

wherein:

-   -   X is —CH₂— or —O—;    -   Y is

-   -   R¹, R², R³, and R⁴ are each independently selected from hydrogen        or halo;    -   R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,        C₀-C₄(C₃-C₆cycloalkyl) or C₁-C₆heteroalkyl;    -   R⁶ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl or        C₀-C₄(C₃-C₆cycloalkyl);    -   R⁷ and R⁸ are each independently selected from hydrogen or        C₁-C₆alkyl;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, X is —O—. In some embodiments, wherein X is —CH₂—.

In some embodiments, Y is

In some embodiments, Y is

In some embodiments, X is —O— and Y is

In some embodiments, X is —O— and Y is

In some embodiments, R⁵ is C₁-C₆alkyl. In some embodiments, R⁵ isselected from the group consisting of methyl, ethyl, propyl and butyl.In some embodiments, R⁵ is propyl. In some embodiments, R⁵ isC₁-C₆allcyl or C₁-C₆haloalkyl. In some embodiments, R⁵ isC₁-C₆haloalkyl. In some embodiments, R⁵ is selected from the groupconsisting of —CH₂F, CHF₂ or CF₃. In some embodiments, R⁵ is CH₂F.

In some embodiments, R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. Insome embodiments, R⁶ is C₁-C₆haloallcyl. In some embodiments, R⁶ is—CH₂CF(CH₃)₂.

In some embodiments, R⁷ and R⁸ are each independently selected fromhydrogen or C₁-C₆alkyl. In some embodiments, R⁷ is methyl and R⁸ ishydrogen.

In some embodiments, the present invention provides a compound ofFormula I(a):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen or halo. In some embodiments, R¹, R², R³ and R⁴ arehydrogen. In some embodiments, R¹, R², R³ and R⁴ are hydrogen or fluoro.

In some embodiments, R⁵ is C₁-C₆alkyl. In some embodiments, R⁵ isselected from the group consisting of methyl, ethyl, propyl and butyl.In some embodiments, R⁵ is propyl.

In some embodiments, R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. Insome embodiments, R⁶ is C₁-C₆haloalkyl. In some embodiments, R⁶ is—CH₂CF(CH₃)₂.

In some embodiments, R⁷ and R⁸ are each independently selected fromhydrogen or C₁-C₆alkyl. In some embodiments, R⁷ is methyl and R⁸ ishydrogen.

In some embodiments, the present invention provides a compound ofFormula I(b):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen or halo. In some embodiments, R¹, R², R³ and R⁴ arehydrogen. In some embodiments, R¹, R², R³ and R⁴ are hydrogen or fluoro.

In some embodiments, R⁵ is C₁-C₆alkyl. In some embodiments, R⁵ isselected from the group consisting of methyl, ethyl, propyl and butyl.In some embodiments, R⁵ is propyl.

In some embodiments, R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. Insome embodiments, R⁶ is C₁-C₆haloalkyl. In some embodiments, R⁶ is—CH₂CF(CH₃)₂.

In some embodiments, R⁷ and R⁸ are each independently selected fromhydrogen or C₁-C₆alkyl. In some embodiments, R⁷ is methyl and R⁸ ishydrogen.

In some embodiments, the present invention provides a compound ofFormula I(c):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen or halo. In some embodiments, R¹, R², R³ and R⁴ arehydrogen. In some embodiments, R¹, R², R³ and R⁴ are hydrogen or fluoro.

In some embodiments, R⁵ is C₁-C₆alkyl or C₁-C₆haloalkyl. In someembodiments, R⁵ is C₁-C₆haloalkyl. In some embodiments, R⁵ is selectedfrom the group consisting of —CH₂F, CHF₂ or CF₃. In some embodiments, R⁵is CH₂F.

In some embodiments, R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. Insome embodiments, R⁶ is C₁-C₆haloalkyl. In some embodiments, R⁶ is—CH₂CF(CH₃)₂.

In some embodiments, R⁷ and R⁸ are each independently selected fromhydrogen or C₁-C₆alkyl. In some embodiments, R⁷ is methyl and R⁸ ishydrogen.

In some embodiments, the present invention provides a compound ofFormula I(d):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹, R², R³, and R⁴ are each independently selectedfrom hydrogen or halo. In some embodiments, R¹, R², R³ and R⁴ arehydrogen. In some embodiments, R¹, R², R³ and R⁴ are hydrogen or fluoro.

In some embodiments, R⁵ is C₁-C₆alkyl or C₁-C₆haloalkyl. In someembodiments, R⁵ is C₁-C₆haloalkyl. In some embodiments, R⁵ is selectedfrom the group consisting of —CH₂F, CHF₂ or CF₃. In some embodiments, R⁵is CH₂F.

In some embodiments, R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆haloalkyl. Insome embodiments, R⁶ is C₁-C₆haloalkyl. In some embodiments, R⁶ is—CH₂CF(CH₃)₂.

In some embodiments, R⁷ and R⁸ are each independently selected fromhydrogen or C₁-C₆alkyl. In some embodiments, R⁷ is methyl and R⁸ ishydrogen.

In some embodiments, the present invention provides a compound which hasthe chemical structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound which hasthe chemical structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound which hasthe chemical structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound which hasthe chemical structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compositioncomprising a compound of any of the Formulae described herein and apharmaceutically acceptable carrier. In some embodiments, the carrier issuitable for oral delivery.

In some embodiments, the present invention provides a method fortreating a disorder mediated by the estrogen receptor in a patient,which comprises administering to the patient a therapeutically effectiveamount of any of the Formulae described herein, optionally in apharmaceutically acceptable carrier. In some embodiments, the disorderis breast cancer.

In some embodiments, the disorder is selected from the group consistingof ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bonecancer, uterine cancer and endometriosis.

In some embodiments, the method further comprises administeringacompound of the present invention in combination or alternation withanother anti-cancer agent for the treatment of cancer.

In some embodiments, the method further comprises administering thecompound in combination or alternation with an estrogen or a partialestrogen receptor antagonist for the treatment of a postmenopausaldisorder. In some embodiments, the patient is a human.

As used herein, the term “combination” means simultaneous or sequentialadministration of two or more therapeutic agents. In some embodiments, acompound of any of the Formulae described herein can be administeredbefore, during or after administration of an additional therapeuticagent, for example, an estrogen or a partial estrogen receptorantagonist.

In some embodiments, the present invention provides a compound of any ofthe Formulae described herein for use in medical treatment.

In some embodiments, the present invention provides a compound of any ofthe Formulae described herein for use in treating a disorder selectedfrom the group consisting of ovarian cancer, endometrial cancer, vaginalcancer, lung cancer, bone cancer, uterine cancer and endometriosis. Insome such embodiments, the disorder is breast cancer.

In some embodiments, the present invention provides a compound of any ofthe Formulae described herein for use in combination with an estrogen ora partial estrogen receptor antagonist for the treatment of apostmenopausal disorder.

In some embodiments, the present invention provides a compound of any ofthe Formulae described herein for use in the manufacture of a medicamentfor treating a disorder selected from the group consisting of ovariancancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer,uterine cancer and endometriosis. In some such embodiments, the disorderis breast cancer.

In some embodiments, the present invention provides a compound of any ofthe Formulae described herein for use in the manufacture of a medicamentfor treating a disorder selected from the group consisting of ovariancancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer,uterine cancer and endometriosis, wherein the medicament is formulatedfor use in combination with an estrogen or a partial estrogen receptorantagonist for the treatment of a postmenopausal disorder.

Preparation of Compounds

Compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.See, e.g., Synthetic Schemes below. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

Compounds provided herein may be isolated and purified by known standardprocedures. Such procedures include (but are not limited to)recrystallization, column chromatography or HPLC. The following schemesare presented with details as to the preparation of representativecompounds of Formula I that have been listed herein. The compoundsprovided herein may be prepared from known or commercially availablestarting materials and reagents by one skilled in the art of organicsynthesis.

The following non-limiting Schemes and Examples for the preparation ofrepresentative compounds are exemplary of the methods used to preparethe compounds of Formula I. General processes for preparing compounds ofthe instant invention are provided as further embodiments of theinvention and are illustrated in the following Schemes. In the Schemes,unless indicated to the contrary, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ andR⁸ are as defined hereinabove.

The following abbreviations may be used in the Examples below: aq.(aqueous); ACN (acetonitrile); CSA (camphorsulfonic acid); d (day ordays); DCM (dichloromethane); DEA (diethylamine); DHP (dihydropyran);DMF (N,N-dimethylformamide); DIPEA (N,N-diisopropylethylamine); DMAP(4-dimethylaminopyridine); DMSO (dimethyl sulphoxide); EA (ethylacetate); ee (enantiomeric excess); equiv. (equivalent); ethanol (EtOH);h (hour or hours); Hex (hexanes); HPLC (high-performance liquidchromatography); IPA (isopropyl alcohol); KHMDS (potassiumbis(trimethylsilyl)amide); LAH (lithium aluminum hydride); LCMS (liquidchromatography-mass spectrometry); LDA (lithium diisopropylamide);LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); min (minuteor minutes); NMR (nuclear magnetic resonance); Pd/C (palladium oncarbon); PPh₃O (triphenylphosphine oxide); Pt/C (platinum on carbon); rb(round-bottomed); Rf (retention factor); rt or RT (room temperature); SM(starting material); TEA (triethylamine); THF (tetrahydrofuran); THP(tetrahydropyran); TLC (thin layer chromatography); TsOH(p-toluenesulfonic acid or tosylic acid); and UV (ultraviolet).

Additional embodiments within the scope provided herein are set forth innon-limiting fashion elsewhere herein and in the examples herein below.It should be understood that these examples are for illustrativepurposes only and are not to be construed as limiting in any manner.

The following non-limiting Schemes and examples are illustrative of thepresent disclosure:

As exemplified in Scheme A, key intermediates for the synthesis ofcompounds of Formula I can be synthesized from readily availablefunctionalized azetidines A-1 and A-4.

Compound A-2 can be prepared by direct alkylation of A-1 or itsO-protected analog using a suitably functionalized alkylating agentcontaining a moiety, such as LCH₂R⁵ under amine alkylation conditions,wherein L is a leaving group, such as halide (e.g., Br, Cl, I) or otherleaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate,tresylate and the like. Compound A-2 can also be prepared by reductiveamination of A-1 with HC(O)R⁵ in the presence of hydrogen and ahydrogenation catalyst, such as Pt, Pd and the like or in the presenceof weak acid such as AcOH and a reducing agent such as NaHB(OAc)₃ andthe like. Alternatively, A-2 is prepared by reacting XC(O)R⁵, where X isa leaving group, with A-4 under amide forming conditions to form theamidoketone, A-5, followed by reduction of the resulting amidoketone A-5using reducing agents known in the art, such as LAH and the like.Nucleophilic aromatic substitution by A-2 of a halide on afunctionalized benzaldehyde A-3 by either aryl nucleophilic substitution(for fluoro-substituted A-3) or via Ullman coupling conditions (foriodo-substituted A-3) under conditions known in the art gives rise to akey intermediate A-7, wherein X is O. Similarly, the correspondingintermediate A-7 where X is S can be prepared by preparing the halidesfrom a azetidine A-1 under nucleophilic substitution reactionconditions, using, for example, hydrochloric acid or hydrobromic acid orhydroiodic acid to form the corresponding chloride, bromide or iodide,respectively, or by reacting azetidine A-1 with an inorganic acidhalide, such as SOCl₂, PCl₅, PCl₃, POCl₃, and the like to form thecorresponding chloride. The product thereof is reacted with a sulfide,such as sodium hydrogen sulfide or sodium thioacetate and the like toform the corresponding thiol or thio ester. The thiol or thio ester isreacted with suitably functionalized alkylating agent containing amoiety, such as LCH₂R⁵ under amine alkylation conditions, wherein L is aleaving group, such as halide (e.g., Br, Cl, I) or another leavinggroup, such as OTs, OBs, ONs, OMs, triflate, nonaflate, tresylate andthe like, and the resulting product is reacted with A-3 to form thecompound of A-7, wherein X is S.

To form compounds wherein X is CH₂, amidoketone A-5 can be coupled toester A-6 via the phosphonium salt of A-6 in a Wittig reaction underWittig forming conditions to form the alkene A-6.1.

Reduction of the resulting alkene followed by reduction of the amide andester functions under reducing conditions known in the art provides thebenzylic alcohol A-6.2.

Oxidation of the benzyl alcohol using oxidizing agents known in the artsuch as copper chromite; DMSO; Collins' reagent; Corey's reagent;pyridinium dichromate; sodium dichromate in water; and the like or DMSO,dicyclohexylcarbodiimide and anhydrous phosphoric acid under Moffattoxidation conditions or anhydrous phosphoric acid and oxalyl chlorideunder Swern oxidation conditions and the like furnishes the aldehydeA-7, wherein X is CH₂.

As exemplified in Scheme B, key intermediates for the synthesis ofcompounds of Formula I can be synthesized from a readily availablefunctionalized phenol B-1. In Step 1, compound B-2 can be prepared bydirect alkylation of B-1 by using a suitably functionalized alkylatingagent containing a moiety, such as LG₁CH₂CH₂OH under phenol alkylationconditions, wherein LG₁ is a leaving group, such as a halide (e.g., Br,Cl, I) or other leaving group, such as OTs, OBs, ONs, OMs, triflate,nonaflate, tresylate and the like. In one embodiment, the phenolalkylating conditions include the use of a base and an organic solventoptionally at an elevated temperature. In one embodiment, the base iscesium carbonate. In one embodiment, the organic solvent isN,N-dimethylformamide. In Step 2, the B-2 alcohol group can be convertedto a leaving group LG₂ by using conditions known to one skilled in theart. The leaving group, LG₂, can be a halide (e.g., Br, Cl, I) or otherleaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate,tresylate and the like. In one embodiment, B-2 is treated withmethanesulfonyl chloride; a base, such as triethylamine; an organicsolvent, such as dichloromethane, at a reduced temperature of about 0°C. In Step 3, an amine, B-4, is treated with B-3, a base and an organicsolvent at an elevated temperature to generate the amine, B-5, accordingto conditions known to those skilled in the art. In one embodiment, thebase is potassium carbonate. In one embodiment, the organic solvent isacetonitrile. In one embodiment, the amine, B-4, is in the form of asalt. In one embodiment, B-4 is a hydrochloride salt. In Step 4,compound B-5 is formylated according to conditions known to those ofskill in the art. In one embodiment, B-5 is treated with a base andtetramethylethylenediamine at a reduced temperature followed byN,N-dimethylformamide at room temperature to generated B-6. In oneembodiment, the base is n-butyllithium. In one embodiment, the reducedtemperature is about −78° C. See, WO 2005/080380.

As exemplified in Scheme C, key intermediates for the synthesis ofcompounds of Formula I can be synthesized from a readily availableketone C-1. In Step 1, C-1 is treated with an amine, such as(R)-(+)-1-phenylethylamine; an organic solvent such as dichloromethaneand a reducing reagent, such as sodium triacetoxyborohydride optionallyat a reduced temperature to generate amine, C-2. In Step 2, amine C-2 isdeprotected according to methods known to those skilled in the art. InStep 2, C-2 is treated with a catalyst such as 20% Pd(OH)₂ on carbon wetwith water; an organic solvent, such as methanol and hydrogen gas atabout 50 psi to generate the indole C-3.

As also exemplified in Scheme C, key intermediates for the synthesis ofcompounds of Formula I can be synthesized from a readily availablealcohol C-4. In Step 3, the C-4 alcohol group can be converted to aleaving group LG₃ by using conditions known to one skilled in the art.The leaving group, LG₃, can be a halide (e.g., Br, Cl, I) or otherleaving group, such as OTs, OBs, ONs, OMs, triflate, nonaflate,tresylate and the like. In one embodiment, C-4 is treated withtrifluoromethanesulfonic anhydride; a base, such as 2,6-lutidine; anorganic solvent, such as dichloromethane, at a reduced temperature ofabout 0° C. In Step 4, amine C-3 is treated with C5, a base, and anorganic solvent according to methods known to one skilled in the art. Inone embodiment, C-3 is treated with C-5, a base such asdiisopropylethylamine and organic solvents such as dichloromethane and1,4-dioxanes at an elevated temperature of about 90° C. to generate C-6.

As exemplified in Scheme D, compounds of Formula I can be synthesizedfrom amine C-6 and an aldehyde such as D-1 using Pictet-Spenglerreaction conditions known to those of skill in the art. For example,amine C-6 is treated with aldehyde D-1 in an anhydrous solvent such astoluene; an acid such as glacial acetic acid; molecular sieves, anitrogen atmosphere in the dark at an elevated temperature of about 80°C. to generate compounds of Formula I.

Section 1: Preparation of Aldehydes EXAMPLE 1 Preparation of2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)-benzaldehyde

Step 1. Preparation of 2-(3,5-difluorophenoxy)ethanol

A suspension of 3,5-difluorophenol (5.07 g, 39.0 mmol, 1.0 equiv.),2-bromoethanol (4.14 mL, 58.5 mmol, 1.5 equiv.) and cesium carbonate(19.05 g, 58.5 mmol, 1.5 equiv.) in DMF (100 mL) was heated to 90° C.for 12 h. TLC (10% EA/Hex) indicated the reaction was nearly complete.The reaction was diluted with EA (200 mL) and washed with water (3×100mL), brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford the product (4.86 g, 71.6%).

¹H NMR (300 MHz, CDCl₃), δ 6.46-6.40 (m, 3H), 4.05 (t, J=4.2 Hz, 2H),3.99-3.94 (m, 2H), 1 94 (t, J=6.0 Hz, 1H).

Step 2. Preparation of 2-(3,5-difluorophenoxy)ethyl methanesulfonate

Mesyl chloride (0.77 mL, 9.9 mmol, 1.0 equiv.) was added over 10 minutesto a solution of 2-(3,5-difluorophenoxy)ethanol (1.66 g, 9.5 mmol, 1.0equiv.) and triethylamine (1.80 mL, 12.9 mmol, 1.4 equiv.) in DCM (120mL.) at 0° C. The reaction was stirred at 0° C. for 1 h. TLC (5%MeOH/DCM) indicated the reaction was complete. Saturated sodiumbicarbonate solution was added to the reaction and stirred at 0° C. for30 minutes. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The residue wasused directly without purification.

¹H NMR (300 MHz, CDCl₃), δ 6.50-6.43 (m, 3H), 4.56 (t, J=4.8 Hz, 2H),4.22 (t, J=4.8 Hz, 2H), 3.08 (s, 3H).

Step 3. Preparation of1-(2-(3,5-difluorophenoxy)ethyl)-3-(fluoromethyl)azetidine

A suspension of 2-(3,5-difluorophenoxy)ethyl methanesulfonate (2.20 g,8.7 mmol, 1.0 equiv.), potassium carbonate (2.65 g, 19.2 mmol, 2.2equiv.), 3-(fluoromethyl)azetidine hydrochloride (1.11 g, 8.8 mmol, 1.0equiv.) in CH₃CN was heated at 82° C. with vigorous stirring overnight.TLC (5% MeOH/DCM) indicated a new spot and a spot that has the same Rfas the mesylate. LCMS indicated that the desired mass was present. Thesolid was filtered off and the filtrate was concentrated to afford asemi-solid, which was dissolved in DCM and loaded onto a silica gelcolumn (25 g cartridge, 50-100% EA/Hex) to afford the title compound asa pale yellow oil (1.65 g, 77.1%).

¹H NMR (300 MHz, CDCl₃), δ 6.45-6.37 (m, 3H), 4.50 (dd, J=47.7, 5.4 Hz,2H), 3.92 (t, J=5.7 Hz, 2H), 3.48 (t, J=7.2 Hz, 2H), 3.14 (t, J=4.2 Hz,2H), 2.93-2.80 (m, 3H).

Step 4. Preparation of2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzaldehyde

A solution of 1-(2-(3,5-difluorophenoxy)ethyl)-3-(fluoromethyl)azetidine(0.60 g, 2.4 mmol, 1.0 equiv.) in dry THF (5 mL) was cooled to −78° C.under a nitrogen atmosphere tetramethyl-ethylenediamine (3.0 mL, 20.0mmol, 8.2 equiv.) and n-butyllithium (1.70 mL, 2.5 mmol, 1.0 equiv.)were added to the mixture and stirred at −78° C. for 30 minutes.N,N-Dimethylformamide (6.0 mL, 3.0 mmol, 1.2 equiv.) was added and thereaction was stirred at RT for 60 min. LCMS indicated the presence ofthe desired mass and TLC (5% MeOH/DCM) indicated there was a faint spotthat has the same Rf as starting material. The reaction was quenchedwith water at 0° C. and extracted with EA (80 mL). The organic layer waswashed with water (3×50 mL), brine, dried over anhydrous sodium sulfate,filtered and concentrated to a light yellow residue. The residue wasdissolved in DCM and loaded onto a silica gel column (25 g cartridge,0-5% MeOH/DCM) to afford the titled compound as a pale yellow thick oil.The general reference for this procedure is WO 2005/080380 pp 44;(PCT/US2005/000024 pp 44).

¹H NMR (300 MHz, CDCl₃), δ 10.19 (s, 1H), 6.48 (d, J=10.5 Hz, 2H), 4.50(dd, J=47.7, 5.4 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.48 (t, J=6.9 Hz,2H), 3.15 (t, J=6.9 Hz, 2H), 2.91-2.80 (m, 3H).

EXAMPL 2 Preparation of4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzaldehyde

Step 1. Preparation of 2-(4-formylphenoxy)ethyl methanesulfonate

Mesyl chloride (0.50 mL, 6.5 mmol, 1.1 equiv.) was added to the solutionof 4-(2-hydroxyethoxy)benzaldehyde (1.01 g, 6.1 mmol, 1.0 equiv.) andtriethylamine (1.1 mL, 7.9 mmol, 1.3 equiv.) in DCM (20 mL) at 0° C.After stirring for 30 minutes, TLC (5% MeOH/DCM) indicated that thereaction was complete. Saturated sodium bicarbonate solution was addedto the reaction and stirred at 0° C. for 30 minutes. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was used directly without purification

¹H NMR (300 MHz, CDCl₃), δ 9.91 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.03(d, J=8.1 Hz, 2H), 4.60 (t, J=4.5 Hz, 2H), 4.34 (t, J=4.5 Hz, 2H), 3.10(s, 3H).

Step 2. Preparation of4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzaldehyde

A suspension of 2-(4-formylphenoxy)ethyl methanesulfonate (1.46 g, 6.0mmol, 1.0 equiv.), potassium carbonate (1.90 g, 13.7 mmol, 2.4 equiv.),3-(fluoromethyl)azetidine hydrochloride (0.73 g, 5.8 mmol, 1.0 equiv.)in CH₃CN was heated at 82° C. with vigorous stirring overnight. TLC (5%MeOH/DCM) indicated a major new spot and a faint new spot less polarthan the product. The reaction was cooled to ambient temperature andconcentrated in vacuo. The residue was diluted with EA (100 mL) andwater (50 mL). The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to afford a yellowresidue which was dissolved in DCM and loaded onto a silica gel column(25 g cartridge, 0-5% MeOH/DCM) to afford the titled compound as a paleyellow oil (0.45 g, 32.4%). Early fractions gave recovered startingmesylate (0.35 g).

¹H NMR (300 MHz, CDCl₃), δ 9.88 (s, 1H), 7.82 (d, J=8.1 Hz, 2H), 6.98(d, J=8.7 Hz, 2H), 4.51 (dd, J=47.4, 5.7 Hz, 2H), 4.05 (t, J=5.4 Hz,2H), 3.50 (t, J=7.4 Hz, 2H), 3.17 (t, J=7.4 Hz, 2H), 2.89-2.85 (m, 3H).

EXAMPLE 3 Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde

Step 1: Preparation of 1-propionylazetidin-3-one

The compound 3-azetidinone hydrochloride (10.000 g, 93.0 mmol, 1.0equiv.), anhydrous 1,2-dichloroethane (200 mL) and diisopropylethylamine(38.9 mL, 223 mmol, 2.4 equiv.) were added to a round bottom flask (500mL) to provide a light yellow suspension. The suspension was sonicatedfor 1 h and then cooled to −10° C. (dry-ice/MeOH) for 10 min. Propionylchloride (9.8 mL, 112 mmol, 1.2 equiv.) was added dropwise to the cooledsuspension to provide an orange solution. The reaction was removed fromthe bath and stirred at room temperature for 16 h. The solvent wasremoved to provide a semi-solid. The semi-solid was suspended into EA(300 mL) and the suspension was filtered. The solid was rinsed with EA(2×100 mL). TLC analysis (10% MeOH/DCM, KMnO₇ stain/Heat) indicatedthere were three spots: Rf: 0.2, 0.5, 0.7. TLC (50% EA/Hex, KMnO₇stain/Heat) indicated there were two spots: Rf: 1, 0.3. The filtrate wasconcentrated, adsorbed onto silica gel (25 g) and chromatographedthrough silica gel (100 g cartridge) with DCM (5 min) then 0-10% MeOHover 15 min. The product came off early from the column in DCM andcontinued to elute from the column with up to 10% MeOH. TLC in bothsolvent systems was carried out to determine if any propionyl chloridewas present in early fractions. Fractions containing product were pooledand concentrated to afford the title compound as a yellow liquid (11.610g, 98.2%).

¹H NMR (300 MHz, CDCl₃) δ: 4.80 (d, J=5.6 Hz, 4H), 2.29 (q, J=7.5 Hz,2H), 2.01 (s, 3H), 1.18 (t, J=7.5 Hz, 3H).

Step 2. Preparation of 1-propylazetidin-3-ol

Lithium aluminum hydride (10.397 g, 273.9 mmol, 3.0 equiv.) wassuspended into THF (200 mL) and cooled in an ice bath. A solution of1-propionylazetidin-3-one (11.610 g, 91.3 mmol, 1.0 equiv.) in THF (100mL) was added dropwise to the reaction mixture via a pressure equalizingaddition funnel over 30 min. The addition funnel was removed. The flaskwas then fitted with a condenser and the reaction was heated at refluxin an oil bath at 75° C. for 16 h. The reaction was cooled in an icebath for 20 min and sodium sulfate decahydrate (Glauber's salt, 25 g)was added in small portions over 20 min. After complete addition, themixture was stirred at room temperature for 2 h. The mixture wasfiltered through a bed of Celite® (2 cm) and the solids rinsed with EA(2×250 mL). The clear solution was concentrated to a pale yellow liquid(9.580 g, 91.1%). NMR indicated the presence of THF and EA. Thismaterial was used without further purification in the preparation of thecompounds of the examples below.

¹H NMR (300 MHz, CDCl₃) δ: 4.39 (pent, J=6 Hz, 1H), 3.62-3.56 (m, 2H),2.90-2.85 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 1.34 (hextet, J=7.2 Hz, 2H),0.87 (t, J=7.8 Hz, 3H).

Step 3. Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde

4-Fluorobenzaldehyde (15.00 g, 120.9 mmol, 0.9 equiv.),1-propylazetidin-3-ol (15.00g, 130.2 mmol, 1.0 equiv.), cesium carbonate(88.40 g, 271.3 mmol, 2.1 equiv.) and N,N-dimethylformamide (284 mL)were mixed together with a Teflon™ stir bar in a 500 mI, round bottomedflask. The flask was sealed and heated in a heat block at 95° C. for 6h. The reaction was analyzed by LCMS to indicate the aldehyde wasconsumed. The suspension was filtered through a sintered glass funneland the solid was washed with ethyl acetate (100 mL). The filtrate wasconcentrated to an orange suspension. The suspension was mixed withwater (200 mL) and ethyl acetate (200 mL) and the organic layer waswashed with water (3×200 mL), brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to an orange liquid (21.74 g, 76.1%).The material was used without further purification.

¹H NMR (300 MHz, CDCl₃), δ 9.87 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 6.86(d, J=8.7 Hz, 2H), 4.86 (quintet, J=5.7 Hz, 1H), 3.85-3.80 (m, 2H),3.13-3.08 (m, 2H), 2.48 (t, J=7.2 Hz, 2H), 1.46-1.34 (m, 2H), 0.91 (t,J=7.2 Hz, 3H).

EXAMPLE 4 Preparation of3-fluoro-4-((1-propylazetidin-3-yl)oxy)benzaldehyde

A solution of 3-fluoro-4-iodobenzaldehyde (0.800 g, 3.2 mmol, 1.0equiv.), 95.0% 1-propylazetidin-3-ol (1.261 g, 10.4 mmol, 3.3 equiv.) inbutyronitrile (1 mL), 1,10-phenanthroline (0.058 g, 0.3 mmol, 0.1equiv.), and cesium carbonate (2.294 g, 7.0 mmol, 2.2 equiv.) were addedto a 48 mL glass pressure bottle. The mixture was degassed and blanketedwith argon (3 times), then Cu(I) iodide (0.616 g, 3.2 mmol, 1.0 equiv.)was added. The mixture was degassed and blanketed with argon anadditional 3 times. The reaction mixture was heated at 120° C. for 40 h.TLC (20% EA/Hex) indicated there was still starting material present.TLC (5% MeOH/DCM) indicated there was a new spot less polar than thestarting aldehyde. The reaction was cooled to room temperature anddiluted with EA and the mixture was sonicated. The mixture was filteredthrough a Celite® pad. The resulting dark brown residue was purified ona silica gel column (12 g, 0-10% MeOH/DCM) to provide a dark oil thatcontained impure product. The material was dissolved in acetonitrile andfurther purified on preparative HPLC (10-90% acetonitrile/H₂O, 20 min)to provide the title compound as a light brown oil (0.073 g, 9.6%).

¹H NMR (CDCl₃, 300 MHz) δ: 9.85 (s, 1H), 7.64-7.58 (m, 2H), 6.83 (t,J=7.9 Hz, 1H), 4.90 (t, J=5.8 Hz, 1H), 3.90-3.85 (m, 2H), 3.18-3.13 (m,2H), 2.50 (t, J=7.5 Hz, 2H), 1.45-1.37 (m, 2H), 0.92 (t, J=7.6 Hz, 3H).

LCMS: [M+1]⁺, 238.5.

Section 2: Preparation of Compounds of Formula I EXAMPLE 5 Preparationof (R)-1-(1H-indol-3-yl)-N—((R)-1-phenylethyl)propan-2-amine

Indole-3-acetone (25.0 g, 144 mmol, 1.0 equiv.) was added to a solutionof (R)-(+)-1-phenylethylamine (23.0 mL, 181 mmol, 1.3 equiv.) indichloromethane (600 mL) under N₂ at 25° C. and the mixture was allowedto stir for 1 hr. The reaction was cooled to 0-5° C. and sodiumtriacetoxyborohydride (100 g, 472 mmol, 3.3 equiv.) was added over 30minutes via powder addition funnel to the ice cooled solution. Theorange solution was stirred for 1 h at 0° C. and then was allowed towarm to RT. The reaction was stirred at RT for 19 h. At this time, ESI+indicated that no indole starting material was present. Saturated NaHCO₃solution (100 mL) was added in 5 mL portions over 15 min at 10° C. withvigorous stirring. The solution was stirred for 15 min and sat. Na₂CO₃solution (200 mL) was added over 15 minutes. Solid K₂CO₃ (9 g) was addedin 3 g portions at which point the aqueous layer was pH 12 and bubbleshad stopped forming. The layers were filtered and separated. The redorganic layer was washed with sat. aq. NaHCO₃ (2×100 mL). The aqueouslayers were combined and extracted with DCM (2×100 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to givethe crude product (49 g). TLC (90:10 DCM:MeOH) showed four spots(Rf=0.63, 0.50, 0.16, 0.26), two of which were the separateddiastereomeric major products (Rf=0.16 and 0.26). The crude was adsorbedonto silica gel and purified via flash chromatography (330 g cartridge,0-100% EA:Hex). Fractions containing the R,R diastereomer were pooledand purified a second time with the same flash chromatography conditionsto afford 24 g of product (˜82% ee). Previous successful separation wasachieved by a silica gel:crude ratio of 40:1, so the mixture was dividedinto 3 portions and separated on 3×330 g silica gel cartridges (0-40%EA/Hex for 20 min, isocratic 40% EA/Hex 40 min). All fractionscontaining the desired product were >99% diastereomerically pure. Purefractions were concentrated and pooled to yield(R)-1-(1H-indol-3-yl)-N—((R)-1-phenylethyl)-propan-2-amine as an orangesemi-solid (11.91 g, 29.6%).

¹H NMR (CDCl₃, 300 MHz) R,R diastereomer: δ 0.96 (d, J=6.6 Hz, 3H), 1.30(d, J=6.6 Hz, 3H), 2.68 (q, J=7.2 Hz, 1H), 2.97 (m, 2H) 4.00 (q, J=6.3Hz, 1H), 7.43-6.97 (m, 10H), 7.96 (br s, 1H). R,S diastereomer: δ 1.11(d, J=5.7 Hz, 3H), 1.30 (d, J=5.4 Hz, 3H) 2.80 (m, 3H), 3.92 (q, J=6.9Hz, 1H), 6.93-7.40 (m, 10H), 8.13 (br s, 1H); the aromatic region wasdifficult to distinguish from the R,R diastereomer due to lack ofpurity.

LCMS: ES+ [M+H]+ 279.0.

EXAMPLE 6 Preparation of (2R)-1-(1H-indol-3-yl)propan-2-amine

The compound (R)-1-(1H-indol-3-yl)-N—((R)-1-phenylethyl)propan-2-amine(11.91 g, 42.8 mmol, 1.0 equiv.) was dissolved in methanol (250 mL) andadded to a 2 L Parr bottle and the solution was sparged with N₂ for 10min. 20% Pd(OH)₂ on carbon wet with water (10.71 g, 76.3 mmol, 1.8equiv.) was added and the bottle was pressurized with 50 psi of hydrogenand shaken in a Parr apparatus for 22 h, LCMS analysis indicated thatthe reaction was completed. The suspension was filtered through Celite®and concentrated to remove MeOH. The crude was dissolved into DCM andwashed with saturated Na₂CO₃ solution (50 mL) and the aqueous layer wasextracted with DCM (2×50 mL). The organic layers were combined, dried,and concentrated to yield (2R)-1-(1H-indol-3-yl)propan-2-amine as alight brown solid that did not require further purification (6.68 g,89.6%).

¹H NMR (CDCl₃, 300 MHz) δ 1.17 (d, J=6.6 Hz, 3H), 2.66 (dd, J=8.4, 14.7Hz, 1H), 2.88 (dd, J=5.4, 14.1 Hz, 1H), 3.27 (sextet, J=1.5 Hz, 1H),7.05-7.22 (m, 3H), 7.37 (d, J=7.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 8.00(br s, 1H).

LCMS: ES+ [M+H]+ 174.9.

EXAMPLE 7 Preparation of 2-fluoro-2-methylpropanol

Methyl 2-fluoro-2-methylpropionate (5.01 g, 40.5 mmol, 1.0 equiv.) wasadded dropwise over 15 min to a stirred suspension of lithium aluminumhydride (2.50 g, 65.9 mmol, 1.6 equiv.) in anhydrous diethyl ether (100mL) cooled in an ice bath. After 2 hours, 2.0 mL water, 2.0 mL 15% w/vNaOH, and 5.0 mL water were added sequentially dropwise. After 15 min,the white suspension was diluted with DCM, gravity filtered throughCelite®, and the solids were washed with DCM. The filtrate wasconcentrated (200 mbar, 25° C.) to afford 2-fluoro-2-methylpropanol as acolorless oil (2.09 g, 56.1%).

¹H NMR (300 MHz, CDCl₃) δ 1.34 (d, J=21.3 Hz, 6H), 1.95 (br t, 1H), 3.56(dd, J=6.6, 20.7 Hz, 2H).

EXAMPLE 8 Preparation of 2-fluoro-2-methylpropyltrifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (5.0 mL, 29.7 mmol, 1.3 equiv.) wasadded dropwise to a 0° C. solution of 2-fluoro-2-methylpropanol (2.090g, 22.7 mmol, 1.0 equiv.) and 2,6 lutidine (3.40 mL, 29.4 mmol, 1.3equiv.) in DCM (25 mL) over 30 minutes. After 2 hours, the red solutionhad turned light brown. TLC (20:80 EA:Hex, KMnO₄ stain) indicated thatthe starting material was not present. The reaction mixture was washedwith 1M HCl solution (2×20 mL) and sat. NaHCO₃ solution (2×20 mL). Theaqueous layers were each back extracted with DCM (20 mL). The combinedorganic layers were dried with Na₂SO₄, filtered and concentrated underreduced pressure (150 mbar, 25° C.) to afford 2-fluoro-2-methylpropyltrifluoromethanesulfonate as a red oil (4.39 g, 86.3%).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (d, J=20.4 Hz, 6H), 4.41 (d, J=18.6 Hz,2H). ¹⁹F NMR (282 MHz, CDCl₃) δ −147.1, −74.5.

EXAMPLE 9 Preparation of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine

The compound 2-fluoro-2-methylpropyl trifluoromethanesulfonate (9.587 g,42.8 mmol, 1.1 equiv.) (solution in DCM, 16% DCM by wt%, 11.4384 g) wasadded to a solution of (2R)-1-(1H-indol-3-yl)propan-2-amine (6.680 g,38.3 mmol, 1.0 equiv.), anhydrous 1,4-dioxanes (60.000 ml, 701.4 mmol,18.3 equiv.), and freshly-distilled diisopropylethylamine (8.500 ml,48.8 mmol, 1.3 equiv.). The dark brown solution was heated at 90° C. for3 hours. After 3 h, LCMS indicated that a small amount of indolaminestarting material was still present. TLC (10% MeOH/DCM) indicatedtriflate (Rf=0.54) had been used up. NMR of unused triflate SM (286-30)indicated the triflate had not decomposed overnight, so another 0.1equiv (0.9883 g, 13% DCM wt %, 0.8563 g triflate SM) was added and thereaction was heated for 2 h at 90° C. LCMS indicated the reaction hadcompleted and TLC (10% MeOH/DCM) showed one spot (Rf=0.24) (TLC with 50%EA/Hex, 1 streaked spot Rf<=0.12, another spot at Rf=0). EtOAc (50 mL)was added and the solution was washed with NaHCO₃ (2×50 mL) and thecombined aqueous layer was washed with EtOAc (50 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure. The crude (brown oil, 14.8 g) was purified via flash silicachromatography (240 g cartridge, 0-100% EA/Hex). The desired producteluted as a long tailing peak. Pure fractions were concentrated to yield(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(4.211 g, 17.0 mmol) as a dark yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.10 (d, J=6.3 Hz, 3H), 1.34 (dd, J=3.0, 21.9Hz, 6H), 2.68-2.95 (m, 4H), 3.02 (sextet, J=6.6 Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 7.26-7.11 (m, 2H), 7.36 (d, J=6.9 Hz, 1H), 7.62 (d, J=7.5 Hz,1H), 8.18 (br s, 1H). ¹⁹F NMR (282 MHz, CDCl₃) δ −144.2. m/z: ES+ [M+H]+249.0.

EXAMPLE 10 General Procedure for Preparation of thetetrahydro-1H-pyrido[3,4-b]indole Series

4-(2-(3-(Fluoromethypazetidin-1-yl)ethoxy)benzaldehyde (0.087 g, 0.4mmol, 1.3 equiv.) was added to a solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(0.070 g, 0.3 mmol, 1.0 equiv.) in anhydrous toluene (1.50 mL) andglacial acetic acid (0.100 mL, 1.7 mmol, 6.2 equiv.). Molecular sieveswere added and the solution was stirred under N₂ in the dark at 80° C.for 8 hours. The reaction solution was diluted in DCM, filtered, andwashed with saturated Na₂CO₃ solution. The aqueous layer was extractedwith DCM and the combined organic layers were dried over Na₂SO₄. Thesolution was filtered and concentrated. The residue was dissolved intoacetonitrile (2 mL) and filtered through a syringe filter beforepurification via prep LC (40 to 90% ACN:H₂O over 18 min, followed byisocratic 90% ACN for 7 min). Pure fractions were concentrated and driedto afford(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas a white powder (32 mg, 24.3%).

Yields:

Compound Name % Yield(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(3-fluoro-4-((1- 15.4%propylazetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1- 21.5%propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1- 11.1%yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3- 24.3%(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Analytical Data:(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(3-fluoro-4-((1-propylazetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.8 Hz, 3H), 1.10 (d, J=7.2 Hz,3H), 1.27-1.52 (m, 8H), 2.45-2.73 (m, 6H), 3.08 (t, J=6.6 Hz, 2H), 3.29(m, 1H), 3.78 (q, J=7.5 Hz, 2H), 4.66 (quin, J=6.0 Hz, 1H), 5.03 (s,1H), 6.58 (t, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.11-7.30 (m, 4H),7.53 (d, J=7.5 Hz, 1H), 8.08 (br s, 1H). m/z: ES+ [M+H]+ 468.3.

(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.5 Hz, 3H), 1.09 (d, J=7.2 Hz,3H), 1.26-1.50 (m, 8H), 2.45-2.77 (m, 6H), 3.01 (t, J=7.2 Hz, 2H), 3.34(m, 1H), 3.77 (m, 2H), 4.60 (quin, J=5.7 Hz, 1H), 5.03 (s, 1H), 6.64 (d,J=8.1 Hz, 2H), 7.10-7.21 (m, 5H), 7.54 (d, J=7.5 Hz, 1H), 8.19 (br s,1H). m/z: ES+ [M+H]+ 450.2.

(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

¹H NMR (300 MHz, CDCl₃) δ 1.10 (d, J=6.3 Hz, 3H), 1.17 (d, J=10.5 Hz,3H), 1.24 (d, J=10.5 Hz, 3H), 2.38 (dd, J=14.7, 25.8 Hz, 1H), 2.60 (dd,J=3.9, 15.3 Hz, 1H), 2.80-2.917 (m, 4H), 3.07-3.16 (m, 3H), 3.48 (t,J=8.1 Hz, 2H), 3.67 (m, 1H), 3.90 (t, J=6.0 Hz, 2H), 4.50 (dd, J=5.7,41.7 Hz, 2H), 5.19 (s, 1H), 6.39 (d, J=10.5 Hz, 2H), 7.09 (m, 2H), 7.22(m, 1H), 7.50 (m, 2H). m/z: ES+ [M+H]+ 503.8.

(1R,3R)-2-(2-fluoro-2-methylpropyl)-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

¹H NMR (300 MHz, CDCl₃) δ 1.08 (d, J=6.6 Hz, 3H), 1.29 (d, J=21.0 Hz,3H), 1.43 (d, J=21.6 Hz, 3H), 2.51-2.89 (m, 7H), 3.14 (t, J=6.9 Hz, 2H),3.38 (m, 1H), 3.48 (t, J=6.9 Hz, 2H), 3.92 (t, J=5.7 Hz, 2H), 4.50 (dd,J=5.7, 47.4 Hz, 2H), 4.99 (s, 1H), 6.79 (d, J=8.1 Hz, 2H), 7.08-7.28 (m,5H), 7.54 (d, J=6.9 Hz, 1H), 7.72 (br s, 1H). m/z: ES+ [M+H]+ 467.9.

EXAMPLE 11 Preparation of3-(4-bromo-3,5-difluorophenoxy)-1-propylazetidine

To a tetrahydrofuran (10 mL) solution of 1-propylazetidin-3-ol (1.479 g,12.8 mmol, 1.0 equiv.), 4-bromo-3,5-difluorophenol (3.220 g, 15.4 mmol,1.2 equiv.) were added triphenylphosphine (4.042 g, 15.4 mmol, 1.2equiv.), and diisopropyl azodicarboxylate (3.034 ml, 15.4 mmol, 1.2equiv.) at 0 C. The resulting mixture was stirred at room temperaturefor 3 h. TLC analysis (5% MeOH/DCM) indicated that the starting phenolstill was present with strong UV absorbance. The mixture was stirred atroom temp. for an additional 12 h. The mixture was concentrated anddissolved in DCM and loaded on to a silica gel column (40 g, 0-5%MeOH/DCM). Fractions 7-13 were collected and concentrated under reducedpressure to give a white solid. 1HNMR indicated product along withtriphenylphosphine oxide. The residue was dissolved in EA (100 ml,) and4 N HCl in dioxane (10 mL) was added. The mixture was stirred at roomtemperature overnight. The mixture was concentrated to an oil. This oilwas cooled in an ice water bath and diethylether (100 mL) was added atwhich point a white solid formed. The mixture was sonicated and stirred.The white solid was filtered and rinsed with diethylether. The resultingsolid was added sat'd sodium bicarbonate solution and EA and stirred atroom temperature for 30 min and layers were separated. Organic layer waswashed with brine, dried over anhy. sodium sulfate, filtered andconcentrated to afford the title compound as a pale yellow oil.

1HNMR (300 MHz, CDCl3), δ 6.40 (d, J=7.5 Hz, 2H), 4.74-4.67 (m, 1H),3.78 (t, J=7.2 Hz, 2H), 3.07 (dt, J=7.4, 3.0 Hz, 2H), 2.46 (t, J=7.5 Hz,2H), 1.45-1.33 (m, 2H), 0.90 (t, J=7.5 Hz, 3H).

EXAMPLE 12 Preparation of2,6-difluoro-4((1-propylazetidin-3-yl)oxy)benzaldehyde

A solution of 3-(3,5-difluorophenoxy)-1-propylazetidine (0.689 g, 3.0mmol, 1.0 equiv.) in dry THF (5 mL) was cooled to −78 C under nitrogenatmosphere. Tetramethylethylenediamine (3.451 ml, 23.1 mmol, 7.6 equiv.)and n-Butyllithium (2.000 ml, 3.0 mmol, 1.0 equiv.) were addedsequentially by syringe. The mixture was allowed to stir at −78 C for 30min. Anhydrous N,N-Dimethylformamide (7.000 ml, 3.5 mmol, 1.2 equiv.)was then added and the mixture stirred as the it warmed to roomtemperature over 60 min. LCMS indicated desired mass and TLC (5%MeOH/DCM) indicated the reaction was complete. The reaction mixture wascooled in an ice bath and the reaction was quenched with water. Theresulting mixture was extracted with EA (80 mL). The phases wereseparated and the organic layer was washed with water (3×50 mL), brine,dried over anhy. sodium sulfate, filtered and concentrated. The lightyellow residue (half) was dissolved in DCM and loaded to a silica gelplate (20×20×2 mm, 5% MeOH/DCM) to afford the title compound as a lightyellow oil (0.22 g, 28.4%). The second half was dissolved in methanoland purified on a prep-HPLC to afford the title compound as a lightyellow oil (161 mg).

1HNMR (300 MHz, CDCl3), δ 10.19 (s, 1H), 6.36 (d, J=9.9 Hz, 2H),4.82-4.76 (m, 1H), 3.79 (dt, J=7.4, 2.4 Hz, 2H), 3.11 (dt, J=7.4, 2.4Hz, 2H), 2.48 (t, J=7.5 Hz, 2H), 1.46-1.34 (m, 2H), 0.91 (t, J=7.5 Hz,3H).

EXAMPLE 13 Preparation of(1R,3R)-1-(2,6-difluoro-4-((1-propylazetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

See Example 10, above, for the general coupling process of2,6-difluoro-4-((1-propylazetidin-3-yl)oxy)benzaldehyde to prepare thetetrahydro-1H-pyrido[3,4-b]indole pictured above.(1R,3R)-1-(2,6-difluoro-4-((1-propylazetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(0.030 g, 0.1 mmol) was a white solid.

1H NMR (300 MHz, CDCl3) δ 0.91 (t, J=7.5 Hz, 3H), 1.10 (d, J=6.9 Hz,3H), 1.17 (d, J=11.7 Hz, 3H), 1.25 (d, J=11.7 Hz, 3H), 1.39 (sex, J=7.5Hz, 2H), 2.39 (dd, J=15.3 Hz, 25.2 Hz, 1H), 2.46 (t, J=7.5 Hz, 2H), 2.61(dd, J=3.9 Hz, 15 Hz, 1H), 2.86 (dd, J=14.7 Hz, 19.5 Hz, 1H), 3.06 (m,3H), 3.67 (sex, J=6.3 Hz, 1H), 3.77 (dt, J=6.0 Hz, 6.3 Hz, 2H), 4.70(quin, J=5.7 Hz, 1H), 5.20 (s, 1H), 6.27 (d, J=9.9 Hz, 2H), 7.06-7.14(m, 2H), 7.19-7.24 (m, 1H), 7.517 (d, J=9 Hz, 1H), 7.51 (s, 1H).

Compound Name % Yield (1R,3R)-1-(2,6-difluoro-4-((1-propylazetidin-3-15.3% yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Demonstration of the Activity of the Compounds of the Present InventionUsing Sensitive In Vitro Estrogenicity Assays EXAMPLE 12

Representative compounds were tested for their inhibitory activity ofestrogen according to the assay methods described in Hodges-Gallagher,L., Valentine, C. V., El Bader, S. and Kushner, P. J. (2007) “HistoneDeacetylase Inhibitors Enhance the Efficacy of Hormonal Therapy Agentson Breast Cancer Cells and Blocks Anti-estrogen-Driven Uterine CellProliferation” Breast Cancer Res Treat, November; 105(3):297-309.Specifically, MCF-7 cells were transiently transfected with anestrogen-responsive reporter gene, ERE-tk109-Luc. Transfected cells weretreated with antiestrogens in hormone-depleted medium in the presence of100 pM 17β-estradiol (E2) for 22 hours. Luciferase activity wasnormalized to activity of E2 alone and IC₅₀'s were calculated using theleast squares fit method.

A representative result for inhibition of E2-induced transcription inbreast cells (nM) is shown below in tabular form:

Compound IC₅₀ A 2.96 B 4.35 C 10.7 D 10.0 AZD9496 0.2 Lasofoxifene 4.6Fulvestrant 1.4

EXAMPLE 13

Proliferation of MCF-7 breast cancer cells was measured using Cyquant, afluorescent DNA-binding dye (Thermo Fisher Scientific). MCF-7 cells weretreated with antiestrogens in triplicate in hormone-depleted medium for5-7 days in the presence of 100 pM E2. Fluorescent activity wasnormalized to the activity of E2 alone and IC₅₀'s were calculated usingthe least squares fit method.

A representative result for inhibition of E2-stimulated proliferation inbreast cells (nM) is shown below in tabular form:

Compound IC₅₀ A 7.58 B 4.53 C 1.3 D 8.4 AZD9496 1.3 Lasofoxifene 11Fulvestrant 2.1

EXAMPLE 14

Method for performing the alkaline phosphatase (AP) assay. ECC-1 cellswere trypsinized and resuspended in hormone-depleted media and plated ata density of 15k cells per well into a 96-well plate for at least 4hours. Cells were treated with antiestrogens for 3 days and plates weresubsequently frozen at −80° C. Thawed plates were incubated with achromogenic substrate of AP, p-nitrophenyl phosphate (Thermo FisherScientific), for 40 minutes at 40° C. and absorbances were read at 405nm. AP activity was normalized to the activity of E2 alone. This assaywas shown to correlate with the in vivo studies comparing uterine wetweight in ovariectomized rats following treatment with a number ofanti-estrogens. A representative result for induction of AP activity inuterine cells (% E2) is shown below in tabular form:

Compound % E2 A 3.96 B 2.18 C 3.1 D 3.37 AZD9496 35 Lasofoxifene 86Fulvestrant −0.13

EXAMPLE 15

AP activity was assayed as in Example 13 but cells were co-treated with500 pM E2. A representative result for inhibition of AP activity inuterine cells (% E2) observed with 100 nM antiestrogen is shown below intabular form:

Compound % E2 A 3.15 B 1.96 C 2.5 D 4.07 AZD9496 33 Lasofoxifene 83Fulvestrant −2.2

EXAMPLE 16 Detecting ER Degradation

MCF-7 cells were treated with 100 nM anti-estrogen for 24 hours inserum-free medium and protein extracts immunoblotted with D12 antibodyto ERα and β-actin (Santa Cruz Biotechnology). The numbers below theblots represent the optical density of ERα bands of each treatmentrelative to percent vehicle after normalization to β-actin.

Compound B degrades the estrogen receptor in MCF-7 Cells. See FIG. 7.

In-cell westerns were performed by treating cells as above in 96-wellplates for 24 hours and immunostained with MA5-14501 antibody to Elbausing the Colorimetric In-Cell ELISA kit (Thermo Fisher Scientific)according to manufacturer's instructions. IC₅₀'s were calculated usingthe least squares fit method. Error bars represent S.E.M from triplicatewells.

Compound B degrades the estrogen receptor in MCF-7 Cells. See FIG. 2.

EXAMPLE 17 Xenograft Study

Xenograft studies were conducted by the Preclinical Therapeutics Core atthe University of California, San Francisco in accordance with theInstitutional Animal Care and Use Committee (IACUC) guidelines. Clone 18cells (MCF7/Her2/neu) cells were grown in culture and implanted intoathymic ovariectomized nu/nu mice. To stimulate tumor growth 0.36 mgestradiol 90 day release pellets (Innovative Research, Saratoga, Fla.)were implanted along with cells. When tumors reached 150-250 cubicmillimeters the pellets were exchanged for 0.18 mg estradiol 90 dayrelease pellets and divided into groups of six mice per treatment group.One of those groups received vehicle only (0.5% CMC+8% DMSO), andCompound B and Compound C each had 2 groups treated with either 10 or100 mg/kg compound. Compounds were administered by oral gavage twicedaily, except once daily on weekends/holidays for the first 21 days, andonce daily after day 21. Tumors and bodyweight were measured twiceweekly.

Compound B shrinks MCF-7 (HER2/neu) tumors at doses as low as 10 mg/kg.See FIGS. 5A-B.

EXAMPLE 18 Pharmacokinetics

Pharmacokinetics were studied in BALB/c female mice. For each arm, threeBALB/c female mice were given 5 mg/kg of compound in 0.5% CMCformulation by oral gavage. Concentration of compounds in mouse plasmaand their metabolites were analyzed at each time point using LC-MS/MS.The concentrations were adjusted for the free fraction of drug in mouseplasma (method below). Area under the curve was calculated using thetrapezoidal rule for 0-24 hours.

Method for detecting free fraction of drug in plasma: Compounds werescreened for binding to human and mouse plasma (Bioreclamation, IVT)using a rapid equilibrium dialysis device (Thermo Fisher Scientific) andcompounds subsequently detected by LC-MS/MS. Percent free drug equalsthe concentration of compound in buffer chamber divided by that in thetissue fraction chamber×100.

Compound B has high oral bioavailability and half-life in BALB/c nudemice. Compound B also exhibits better 24 hour drug exposure compared toother compounds. See FIGS. 1A-B.

EXAMPLE 19 ER-α Binding

Compounds were screened for their ability to displace a fluorescentlabelled tracer ERα ligand via time resolved fluorescent energy transferusing the LanthaScreen Competitive Binding Assay screening service(Thermo Fisher Scientific).

Specifically, Compounds B and C show comparable activity to fulvestrant,Goodacre Compound 102, and Goodacre Compound 107. Compounds B and C havepotency similar to fulvestrant in blocking estrogen driven geneexpression and proliferation of human breast cancer. See FIG. 2.

1-81. (canceled)
 82. A method of preventing recurrence of a cancer in apatient comprising administering to the patient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein X is —CH₂— or—O—; Y is

R¹ and R² are each hydrogen; R³ and R⁴ are each independently selectedfrom hydrogen and halo, and when one of R³ or R⁴ is halo, the other ofR³ or R⁴ is hydrogen; R⁵ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₀-C₄(C₃-C₆cycloalkyl) or C₁-C₆heteroalkyl; R⁶ ishydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₀-C₄(C₃-C₆cycloalkyl); and R⁷and R⁸ are each independently selected from hydrogen or C₁-C₆alkyl. 83.The method of claim 82, wherein the cancer is selected from breastcancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer,bone cancer, uterine cancer and endometriosis.
 84. The method of claim82, wherein the compound is administered as an adjunctive therapy afteror instead of chemotherapy, radiation, or surgery.
 85. The method ofclaim 84, wherein the compound is administered after surgery.
 86. Themethod of claim 82, wherein the compound is administered prior tosurgery.
 87. The method of claim 83, wherein the cancer is breastcancer.
 88. The method of claim 87, wherein the breast cancer hasprogressed in the presence of endocrine or aromatase therapy.
 89. Themethod of claim 82, wherein X is —O—.
 90. The method of claim 82,wherein Y is


91. The method of claim 82, wherein Y is


92. The method of claim 82, wherein R⁵ is C₁-C₆ alkyl or C₁-C₆haloalkyl.
 93. The method of claim 82, wherein R⁷ and R⁸ are eachindependently selected from hydrogen or C₁-C₆alkyl.
 94. The method ofclaim 82, wherein the compound is of Formula I(a):

or a pharmaceutically acceptable salt thereof.
 95. The method of claim94, wherein R¹, R², R³ and R⁴ are each hydrogen.
 96. The method of claim82, wherein the compound is of Formula I(c):

or a pharmaceutically acceptable salt thereof.
 97. The method of claim96, wherein R¹, R², R³ and R⁴ are each hydrogen.
 98. The method of claim82, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 99. The method of claim82, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 100. The method of claim82, wherein the compound is:

or a pharmaceutically acceptable salt thereof.